WO2015035113A1 - Spirocyclic compounds as tryptophan hydroxylase inhibitors - Google Patents

Spirocyclic compounds as tryptophan hydroxylase inhibitors Download PDF

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Publication number
WO2015035113A1
WO2015035113A1 PCT/US2014/054202 US2014054202W WO2015035113A1 WO 2015035113 A1 WO2015035113 A1 WO 2015035113A1 US 2014054202 W US2014054202 W US 2014054202W WO 2015035113 A1 WO2015035113 A1 WO 2015035113A1
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WIPO (PCT)
Prior art keywords
decane
amino
pyrimidin
biphenyl
methyl
Prior art date
Application number
PCT/US2014/054202
Other languages
French (fr)
Inventor
Stéphane De Lombaert
Daniel R. Goldberg
Kenneth Brameld
Eric Brian Sjogren
Andrew Scribner
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Karos Pharmaceuticals, Inc.
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Publication date
Priority to UAA201603580A priority Critical patent/UA119247C2/en
Priority to NZ717556A priority patent/NZ717556B2/en
Priority to MYPI2016000415A priority patent/MY186265A/en
Priority to KR1020167009029A priority patent/KR102336075B1/en
Priority to JP2016540401A priority patent/JP6470290B2/en
Priority to MX2016002936A priority patent/MX371191B/en
Priority to DK14786383.1T priority patent/DK3041842T3/en
Priority to EP14786383.1A priority patent/EP3041842B8/en
Priority to CN201480060427.9A priority patent/CN105764902B/en
Priority to AU2014315109A priority patent/AU2014315109B2/en
Priority to CA2922933A priority patent/CA2922933C/en
Priority to ES14786383T priority patent/ES2780828T3/en
Application filed by Karos Pharmaceuticals, Inc. filed Critical Karos Pharmaceuticals, Inc.
Priority to LTEP14786383.1T priority patent/LT3041842T/en
Priority to SI201431461T priority patent/SI3041842T1/en
Priority to RS20200059A priority patent/RS59871B1/en
Priority to BR112016004909-8A priority patent/BR112016004909B1/en
Priority to ARP140103327A priority patent/AR097571A1/en
Priority to PL14786383T priority patent/PL3041842T3/en
Priority to EA201690534A priority patent/EA032304B1/en
Publication of WO2015035113A1 publication Critical patent/WO2015035113A1/en
Priority to IL244315A priority patent/IL244315B/en
Priority to PH12016500416A priority patent/PH12016500416B1/en
Priority to CY20201100036T priority patent/CY1122652T1/en
Priority to HRP20200098TT priority patent/HRP20200098T1/en

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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Definitions

  • the present invention is directed to spirocyclic compounds which are inhibitors of tryptophan hydroxylase (TPH), particularly isoform 1 (TPHl), that are useful in the treatment of diseases or disorders associated with peripheral serotonin including, for example,
  • Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that modulates central and peripheral functions by acting on neurons, smooth muscle, and other cell types. 5-HT is involved in the control and modulation of multiple physiological and psychological processes. In the central nervous system (CNS), 5-HT regulates mood, appetite, and other behavioral functions. In the GI system, 5-HT plays a general prokinetic role and is an important mediator of sensation (e.g., nausea and satiety) between the GI tract and the brain. Dysregulation of the peripheral 5-HT signaling system has been reported to be involved in the etiology of several conditions (see for example: Mawe, G. M. & Hoffman, J, . Serotonin Signalling In The Gut- functions, Dysfunctions And Therapeutic Targets. Nature Reviews. Gastroenterology &
  • liver diseases or disorders e.g. Ebrahimkhani, M. R. et al Stimulating Healthy Tissue Regeneration By Targeting The 5-HT2B Receptor In Chronic Liver Disease. Nature Medicine 17, 1668-73 (2011).
  • the large number of pharmaceutical agents that block or stimulate the various 5-HT receptors is also indicative of the wide range of medical disorders that have been associated with 5-HT dysregulation (see for example: Wacker, D. et al Structural Features For Functional Selectivity At Serotonin Receptors, Science (New York N Y.) 340, 615-9 (2013)).
  • the rate-limiting step in 5-HT biosynthesis is the hydroxylation of tryptophan by dioxygen, which is catalyzed by tryptophan hydroxylase (TPH; EC 1.14.16.4) in the presence of the cofactor (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4).
  • TPH tryptophan hydroxylase
  • 6R cofactor 6-R
  • 6R cofactor-L-erythro-5,6,7,8-tetrahydrobiopterin
  • BH4 cofactor
  • the resulting oxidized product, 5 -hydroxy tryptophan (5-HTT) is subsequently decarboxylated by an aromatic amino acid decarboxylase (AAAD; EC 4.1.1.28) to produce 5-HT.
  • AAAD aromatic amino acid decarboxylase
  • TPH belongs to the pterin-dependent aromatic amino acid hydroxylase family.
  • TPH1 and TPH2 Two vertebrate isoforms of TPH, namely TPH1 and TPH2, have been identified.
  • TPH1 is primarily expressed in the pineal gland and non-neuronal tissues, such as entei chromaffin (EC) cells located in the gastrointestinal (GI) tract.
  • TPH2 (the dominant form in the brain) is expressed exclusively in neuronal cells, such as dorsal raphe or myenteric plexus cells.
  • the peripheral and central systems involved in 5-HT biosynthesis are isolated, with 5-HT being unable to cross the blood-brain barrier. Therefore, the pharmacological effects of 5-HT can be modulated by agents affecting TPH in the periphery, mainly TPH1 in the gut.
  • a small number of phenylalanine-derived TPHl inhibitors are known.
  • p- chlorophenylalanine a very weak and unselective irreversible inhibitor of TPH
  • pCPA is distimped centrally and, as a result, its administration has been linked to the onset of depression and other alterations of CNS functions in patients and animals.
  • p-Ethynyl phenylalanine is a more selective and more potent TPH inhibitor than pCPA (Stokes, A, H. el al. p-Ethynylphenylalanine: A Potent Inhibitor Of Tryptophan Hydroxylase. Journal ofNeurochemisiry 74, 2067-73 (2000), but also affects central 5-HT production and, like pCPA, is believed to irreversibly interfere with the synthesis of TPH (and possibly other proteins).
  • the present invention relates to a TPH-inhibiting compound of Formula I:
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a TPH- inhibiting compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the present invention further relates to a method of inhibiting TPH, such as TPH1, by contacting the TPH enzyme with a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the present invention further relates to a method of lowering peripheral serotonin in a patient comprising administering to the patient an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the present invention further relates to a method of treating or preventing a disease in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the present invention further relates to a compound of Formula ⁇ , or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of disease in a patient.
  • the present invention further relates to use of a compound of Formula I or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of disease in a patient.
  • the present invention relates to a TPH-inhibiting compound of Formula I:
  • Ring A is Qj-io cycloalkyl, Ce-ioaryl, 4 to 10-membered heterocycloalkyl, or 5 to 10- membered heteroaryl;
  • L is O or NR 4 ;
  • W is N or CR 5 ;
  • X is N or CR 6 ;
  • Y is N or CR 7 ;
  • R 1 is H, C[-to alkyl, Qj-iocycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, -(CR s R 9 ),,OC(0)R 10 , -(CR 8 R 9 ) p R n R 12 , or -(CR 8 R 9 ) P C(0)NR 1 l R n , wherein said Ci-io alkyl, C3.10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and phenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from F, CI, Br, CN, Cm alkyl, and Ci-4 haloalkyl;
  • R 2 and R 3 are each independently selected from H, CM alkyl, and Ci ⁇ haloalkyl;
  • R 4 is H o Ci- 4 alkyl
  • R 5 and R 6 are each independently selected from H, halo, and C alkyl
  • R 7 is H, C alkyl, C 2-6 alkenyl, C3-io cycloalkyl, Cs-io cycloalkyl-CM alkyl, Ce-io aryl, C 6- io aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, 5-10 membered heteroaryl, (5-10 membered heteroaryl)-C M alkyl, NR 13 R 14 , OR 15 , C(0)R )6 3 S(0) q R 17 , wherein said C alkyl, C 2 -6 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C alkyl, C 6- io aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)- C1-4 alkyl, 5-10
  • R 8 and R 9 are each independently selected from H and Ci-4 alkyl
  • R i0 is Cs-6 alkyl optionally substituted by 1, 2 or 3 substituents independently selected from Ct-6 haloalkyl, C 3- jo cycloalkyl, OR a , and NR c R d ;
  • R 11 and R 12 are each independently selected from H and Ci-6 alkyl
  • R 13 is H or Ci-4 alkyl
  • R 14 is H, Ci- alkyl, C 3 -7 cycloalkyl, C 3- 7 cycloalkyl-Q-4 alkyl, C&-io aryl, Ce-io aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C!-4 alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl)-Ci-4 alkyl, C(0)R bI , C(0)OR al ,
  • R 13 and R 14 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7- membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents
  • Ci- 6 alkyl, C3.7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6- ioaryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, OR al , SR al , C(0)R bl , C(0)NR CI R dl , C(0)OR a) , OC(0)R b! ,
  • R 15 is H, C alkyl, C3 -7 cycloalkyl, C 3- 7 cycloalkyl -C] -4 alkyl, Ce-jo aryl, Ce-io aryl-Cm alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalky ⁇ -C alkyl, 5-10 membered heteroaryl, or (5-10 membered hetei'oaryl)-Ci -4 alkyl, wherein said C alkyl, C3-7 cycloalkyl, C3-7 cycloa!kyl-C[. ⁇ i alkyl, Ce-io aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered
  • heterocycloalkyl (4-10 membered heteiOcycloalkyl)-d -4 alkyl, 5-10 membered heteroaryl, and (5- 10 membered heteroaryl)-C alkyl are each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io ryl, 5-6 membered heteroaryl, CN, OR al , SR a! , C(0)R bI , C(0)NR c! R dl , C(0)OR al , OC(0)R bI ,
  • R 16 is C1.4 alkyl or NR ,8 R 18b wherein said Ci -4 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-!o aryl, 5-6 membered heteroaryl, CN, OR al , SR al , C(0)R bl , C(0)NR cI R di , C(0)OR al , OC(0)R bI , OC(0)NR c!
  • R 17 is Ci-4 alkyl, NR ! 8a R ISb , or OR 18c , wherein said C M alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6 .io aryl, 5-6 membered heteroaryl, CN, OR nt , SR al , C(0)R bl , C(0)NR ci R ⁇ n , C(0)OR l , OC(0)R bl , OC(0)NR cl R dl , NR cl R d ', NR cl C(0)R b) , NR cl C(0)NR c, R dl ,
  • R 18a and R 18b are each independently selected from H and C alkyl wherein said CM alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6 -ioaryl, 5-6 membered heteroaryl, CN, OR al , SR a!
  • R I8ft and R l8b together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1 , 2, or 3 substituents
  • R 18c is H, Ci-6 alkyl, C3-10 cycloalkyl, Q ⁇ cycioalkyl-Cm alkyl, Ce-io aryl, C 6- io ryl-CM alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci- 4 alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl)-Ci-4 alkyl, wherein said CM alkyl, C 3- 7 cycloalkyl, C3-io cycloalkyl-Ci-4 alkyl, Ce-io aryl, Ce-io aryl-Ct ⁇ alkyl, 4-10 membered
  • heterocycloalkyl (4-10 memberedheterocycloalkyl)-Ci.4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl) ⁇ C 1 -4 alkyl are each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, CM alkyl, CM haloalkyl, CN, N0 2 , OR al , SR aI , C(0)R bl , C(0)NR cl R dl , C(0)OR ai ; OC(0)R bl , OC(0)NR cl R dl , NR cl R dl , NR cl C(0)R bl , NR d C(0)OR aI , NR 0l C(O)NR cl R dl , NR cl S(0)R bt , NR cl S(0) 2 R I , NR cl S(0) 2 NR
  • R A is H ⁇ Cy 1 , halo, C alkyl, C2-6 alkenyl, CN, N0 2 , OR 82 , SR a2 , C(0)R b2 , C(0)NR c2 R d2 , C(0)OR a2 , OC(0)R b2 , OC(0)NR c R d2 , NR c2 R d2 , NR c C(0)R b2 , NR c C(0)OR a2 ,
  • 6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 1 , halo, CM alkyl, C 2- 6 alkenyl, C haloalkyl, CN, N0 2 , OR a2 , SR* 2 , C(0)R b2 , C(0)NR c2 R d2 , C(0)OR a2 , OC(0)R b2 , OC(0)NR c2 R d2 ; NR c R d2 , NR c2 C(0)R b2 , NR c2 C(0)OR a2 , NR c C(0)NR c2 R d2 , NR c2 S(0)R b2 , NR c2 S(0) 2 R b2 , NR c2 S(0) 2 R b2 , NR c2 S(0) 2 NR c2 R d2 , S(0)R b2 , S(0)NR c2 R d2
  • 6 alkenyi are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from Cy 2 , halo, Ci-6 alkyl, C 2- 6 alkenyi, C). 6 haloalkyl, CN, N0 2 , OR 33 , SR 33 , C(0)R b3 , C(0)NR c3 R d3 , C(0)OR a3 , OC(0)R b3 , OC(0)NR c3 R d3 , NR c3 R d3 , NR c3 C(0)R b3 , NR c3 C(0)OR a3 , NR c3 C(0)NR c3 R d3 , NR c3 S(0)R b3 , NR c3 S(0)R b3 , NR cl S(0) 2 R b3 , NR c3 S(0) 2 NR c3 R d3 , S(0)R b3 , S(0)NR c3 R
  • R c and R D are each independently selected from H, halo, Ci-6 alkyl, C 2- 6 alkenyi, Ci -6 haloalkyl, CN, N0 2 , OR a4 , SR a4 , C(0)R b4 , C(0)NR c4 R d4 , C(0)OR a4 , OC(0)R 4 , OCCC R ⁇ R" 4 , NR c4 R d4 , NR c4 C(0)R b4 , NR c4 C(0)OR a4 > NR c4 C(0)NR c R d4 ) NR c4 S(0)R b4 , NR c S(0) 2 R M ( NR c4 S(0) 2 NR c4 R d4 J S(0)R b4 , S(0)NR c4 R d4 , S(0) 2 R M , and S(0) 2 NR e4 R d4 ; wherein said Ci.
  • C 2- 6 alkenyi are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from Ce-io ai'yl, C3-io cycloalkyl, 5-10 membered heteroaryl, 4- 10 membered
  • Cy 1 and Cy 2 are each independently selected from Ce-io aryl, C3-io cycloalkyl, 5-10 membered heteroaryl, and 4- 10 membered heterocycloalkyl, each of which is optionally substituted by 1 , 2, 3, 4, or 5 substituents independently selected from R Cy ;
  • each R Cy is independently selected from halo, Ci-6 alkyl, Ci- ⁇ haloalkyl, C 2- 6 alkenyi, C 6 -io aryl, C3-io cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, N0 2 ⁇ OR aS , SR a5 , C(0)R b5 , C(0)NR c5 R 5 , C(0)OR a5 , OC(0)R b5 , OC(0)NR c5 R d5 , NR c5 R ds ,
  • NR c5 C(0)R bS NR c5 C(0)OR a5 , NR c5 C(0)NR c5 R d5 , NR c5 S(0)R b5 , NR c5 S(0) 2 R b5 ,
  • Ci- 6 alkyl, C2-0 alkenyi C6-io aryl, C3-10 cycloalkyi, 5-10 membered heteroaryl, and 4- 10 membered heterocycloalkyl are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from halo, Ci- ⁇ alkyl, CN, N0 2 , OR aS , SR aS , C(0)R b5 , C(0)NR c5 R d5 , C(0)OR aS , OC(0)R b5 , OC(0)NR c5 R d5 , NR e5 R d5 , NR c5 C(0)R b5 , NR c5 C(0)OR
  • each R a , R al , R a2 , R 83 , R a4 , and R a5 is independently selected from H, C
  • haloalkyl C2 -6 alkenyl, Ce-io aryl, C 3- io cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-io aryl-Ci-4 alkyl, C3-10 cycloalkyl-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- alky], or (4-10 membered heterocycloalkyl)-Ci- 4 alkyl, wherein said Ci- ⁇ alkyl, C2 -6 alkenyl, Ce- lo aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-to ryl- C alkyl, C 3 -io cycloa!kyl-Ci-4 alkyl, (5-10 membered heteroaryl)-C[.4 alkyl, and (4-10 membered heterocycloalkyl)- C 1.4 alkyl are
  • each R bl , R b2 , R b3 , R 4 5 and R b5 is independently selected from H, Ci- 6 alkyl, CM
  • haloalkyl C 2 -6 alkenyl, Ce-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4- 10 membered heterocycloalkyl, Ce-io iyl-Ci- alkyl, C 3- ]o cycloalkyl-C alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, or (4-10 membered heterocycloalkyl)-Ci-4 alkyl, wherein said Ci- 6 alkyl, C 2 -6 alkenyl, Cg.
  • 4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, and (4-10 membered heterocycloalkyl)-Ci.4 alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from CM alkyl, halo, CN, OR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 , OC(0)R b6 , OC(0)NR e6 R d6 , NR c6 R d6 , NR c6 C(0)R b6 , NR c6 C(0)NR c6 R 6 ,
  • NR c6 C(0)OR" 6 S(0)R b6 , S(0)NR c6 R d6 , S(0) 2 R b6 , NR c6 S(0) 2 R b6 , NR c6 S(0) 2 NR c6 R d6 , and S(0) 2 NR c6 R d6 ;
  • each R° , R d , R cl , R dl , R c2 , R d2 , R c3 , R d3 , R c4 , R d4 , R cS , and R d5 is independently selected from H, Ci-6 alkyl, CM haloalkyl, C 2- 6 alkenyl, C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-io ryl-CM alkyl, C3-io cycloalkyl-Ci-4 alkyl, (5- 10 membered heteroaryl)-Ci-4 alkyl, or (4-10 membered heteiOcycloalkyl)-Ci- 4 alkyl, wherein said Ci-6 alkyl, C2-0 alkenyl, Ce-io a yl, C3-10 cycloalkyl, 5-10 membere
  • cycloalkyl, 4-7 membered heterocycloalkyl, C 6 -io aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR n6 , OC(0)R b6 ⁇ OC(0)NR c6 R d6 , NR c6 R d6 , NR c6 C(0)R b6 , NR c6 C(0)NR c6 R d6 , NR c6 C(0)OR a6 , S(0)R b6 , S(0)NR c6 R d6 , S(0) 2 R b6 , NR c6 S(0) 2 R b6 , NR c6 S(0) 2 NR c6 R d6 , and S(0) 2 NR c6 R d6
  • R cl and R d! together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci- 6 alkyl, C3.7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6 -io aryl, 5-6 membered heteroaryl, halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 , OC(0)R b6 , OC(0)NR c6 R d6 ⁇ NR e6 R d6 , NR c6 C(0)R b6 , NR c6 C(0)NR c6 R d6 , NR c6 C(0)OR a6 ;
  • Ci- 6 alkyl, C 3 -7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 , 0C(O)R b6 ,
  • R c2 and R d2 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C 3- 7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6 -io aryl, and 5-6 membered heteroaryl, d .
  • R c3 and R d3 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6 -io aryl, 5-6 membered heteroaryl, Ci-6 haloalkyl, halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 , OC(0)R h6 , OC(0)NR e6 R d6 , NR c6 R d6 , NR c6 C(0)R b6 , NR c6 C(0)NR c6 R d£> ,
  • Ci-6 alkyl, C 3- 7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, OR a6 , SR 6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 ,
  • R c4 and R d4 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-to aryl, 5-6 membered heteroaryl, Ci- ⁇ haloalkyl, halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 , OC(0)R b6 , OC(0)NR c6 R d6 , NR c6 R d6 , NR c6 C(0)R b6 , NR c6 C(0)NR c6 R d6 ,
  • Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 , OC(0)R b6 , OC(0)NR c6 R d6 , NR e6 R d6 , NR c6 C(0)R b6 ⁇ NR c6 C(0)NR
  • R° 5 and R d5 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1 , 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6 -io aryl, 5-6 membered lieteroaryl, Ci-e haloalkyl, halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 , OC(0)R 6 , OC(0)NR c6 R d6 , NR c6 R d6 , NR c6 C(0)R b6 , NR c6 C(0)NR e6 R d6 ,
  • each R a6 , R b6 , R c6 , and R d6 is independently selected from H, C ]-4 alkyl, C2-4 alkenyl, C 3 . 7 cycloalkyl, phenyl, 5-6 membered lieteroaryl, and 4-7 membered heterocycloalkyi, wherein said C[-4 alkyl, C 2 .4 alkenyl, C3-7 cycloalkyl, phenyl, 5-6 membered lieteroaryl, and 4-7 membered heterocycloalkyi are each optionally substituted by 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C alkyl, C alkoxy, Ci ⁇ a!kylthio, CM alkylamino, and di(Ci- 4 alkyl)amino;
  • n 1 or 2;
  • p is 1 , 2, or 3;
  • q 1 or 2;
  • any aforementioned 4-10 or 4-7 membered heterocycloalkyi group optionally comprises 1 , 2, or 3 oxo substituents, wherein each oxo substituent that is present is substituted on a ring- forming carbon, nitrogen, or sulfur atom of the 4-10 or 4-7 membered heterocycloalkyi group.
  • the present invention relates to a TPH-inhibiting compound of Formula I:
  • Ring A is C3-10 cycloalkyl, Ce-io aryl, 4 to 10-membered heterocycloalkyl, or 5 to 10- membered heteroaiyl;
  • L is O or NR 4 ;
  • W is N or CR 5 ;
  • X is N or CR 6 ;
  • ⁇ is N or CR 7 ;
  • R 1 is H, CMO alkyl, C 3 -iocycloalkyl, phenyl, -(CR 8 R 9 ) P OC(0)R 10 , -(CR 8 R 9 ) p NR n R 12 , or -(CR 8 R 9 )pC(0)NR n R 12 , wherein said C M 0 alkyl, C 3- to cycloalkyl, and phenyl are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from F, CI, Br, CN, C alkyl, and Ci.4 haloalkyl;
  • R 2 and R 3 are each independently selected from H, CM alkyl, and Ci -4 haloalkyl;
  • R 4 is H or Ci. 4 alkyl
  • R 5 and R 6 are each independently selected from H, halo, and Ci-4 alkyl;
  • R 7 is H, Ci-4 alkyl, C 2 -6 alkenyl, C3-io cycloalkyl, C 3- io cycloalkyl-C alkyl, C6-io aryl, C 6- io aryl-Ci- alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyi)-Ci alkyl, 5-10 membered heteroaiyl, (5-10 membered heteroaryl)-Ci-4 alkyl, NR ,3 R H , OR 15 , C(0)R 16 , S(0)qR i7 , wherein said Ci-4 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C3-iocycloalkyl-Ci-4 alkyl, C 6 -io aryl, C6-io aryl-Ci -4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloal
  • R 8 and R 9 are each independently selected from H and C alkyl
  • R 10 is Ci-6 alkyl optionally substituted by 1, 2 or 3 substituents independently selected from Ci-6 haloalkyl, C 3 .10 cycloalkyl, OR a , and NR c R d ;
  • R 11 and R i2 are each independently selected from H and Ci-6 alkyl
  • R 13 is H or Ci. 4 alkyl
  • R H is H, C1.4 alkyl, C3.7 cycloalkyl, C3-7 cycloalkyl-C)-4 alkyl, Ce-io aryl, C 6 .io aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, 5-10 membered heteroaiyl, or (5-10 membered heteroaryl)-C 1.4 alkyl, C(0)R bl , C(0)OR al ⁇ C(0)NR cI R dI , S(0)R bi , S(0) 2 R bl , or S(0) 2 NR c, R dl ⁇ wherein said CM alkyl, C3-7 cycloalkyl, C 3-7 cycloalkyl-Cf.
  • 4 alkyl, Ce-ioaryl, Ce-io aryl-Cm alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-Ci-4 alkyl are each optionally substituted by 1, 2, or 3 substltuents independently selected from halo, C M alkyl, C haloalkyl, CN, N0 2 , OR al , SR al , C(0)R bl 5 C(0)NR cl R dl , C(0)OR a ⁇ OC(0)R bl , OC(0)NR cl R dl , NR cl R d! , NR ci C(0)R bl , NR cl C(0)OR al ,
  • R 13 and R 14 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7- membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substltuents
  • Ci- 6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substltuents independently selected from halo, CN, OR al , SR al , C(0)R bl , C(0)NR oi R d! 5 C(0)OR al , OC(0)R bl ,
  • R !5 is H, C alkyl, C3-7 cycloalkyl, C 3 - 7 cycloalkyl-Ci-4 alkyl, C 6 -io aryl, C 6 -io aryl-C[-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci- 4 alky], 5-10 membered heteroaryl, or (5-10 membered heteroaryl )-C 1-4 alkyl, wherein said C1-4 alkyl, C 3-7 cycloalkyl, C3-7 cycloalkyl-Ci-4 alkyl, Ce-io aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered
  • heterocycloalkyl (4-10 membered heterocycloalkyl) -C alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-Ci-4 alkyl are each optionally substituted by 1, 2, or 3 substltuents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, 5-6 membered heteroaryl, CN, OR al , SR aI , C(0)R bt , C(0)NR cl R dl , C(0)OR al , OC(0)R bl ,
  • R 16 is C1.4 alkyl or NR i8a R 18b wherein said CM alkyl is optionally substituted by 1, 2, or 3 substltuents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, 5-6 membered heteroaryi, CN, OR al , SR al , C(0)R bi , C(0)NR cl R dl , C(0)OR al , OC(0)R i , OC(0)NR c, R dl , NR c!
  • R 17 is Ci-4 alkyl, NR 18a R !8b , or OR ISe , wherein said Ci -4 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6 -]o aryl, 5-6 membered heteroaryi, CN, OR al , SR al , C(0)R bl , C(0)NR cl R dt , C(0)OR al , OC(0)R bl , OC(0)NR cl R dl , NR cl R dI , NR c) C(0)R bl , NR ci C(0)NR cl R dl ,
  • R I8a and R !8b are each independently selected from H and CM alkyl wherein said CM alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, 5-6 membered heteroaryi, CN, OR ai , SR al , C(0)R bl 5 C(0)NR cl R dl , C(0)OR al , OC(0)R ⁇ OC(0)NR cl R di , NR ⁇ R 4 ", NR cl C(0)R b3 ⁇ 4 , NR c, C(0)NR d R dl ; NR c4 C(0)OR a! , S(0)R bl , S(0)NR cl R dl , S(0) 2 R bl , NR c, S(0) 2 R l ,
  • Ci -6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, and 5-6 membered heteroaryi are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, OR al , SR a1 , C(0)R b! , C(0)NR c! R dl J C(0)OR al , OC(0)R l ,
  • R is H, Cue alkyl, C3-10 cycloalkyl, C3- cycloalkyl-Ci-4 alkyl, Ce-io aryl, C6-so aryl-Ci. 4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C f .
  • R A is H, Cy 1 , halo, Ci-e alkyl, C 2-6 alkenyl, CN, N0 2f OR* 2 , SR a2 , C(0)R b2 s C(0)NR c2 R d2 , C(0)OR a2 , OC(0)R b2 , OC(0)NR c R 2 , NR c2 R d2 , NR c C(0)R 2 , NR c2 C(0)OR a2 ,
  • Ci -6 alkyl and C 2 . 6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 1 , halo, O-e alkyl, C 2 .
  • R B is H, Cy 2 , halo, Ci- 6 alkyl, C 2 . 6 alkenyl, Ci- 6 haloalkyl, CN, N0 2 , OR a3 , SR 3 , C(0)R b3 , C(0)NR c3 R d3 , C(0)OR n3 , OC(0)R b3 , 0C(0)NR c3 R d3 , NR c3 R d3 , NR c3 C(0)R b3 , NR c3 C(0)OR a3 , NR c3 C(0)NR 3 R d3 , NR c3 S(0)R b3 , NR c3 S(0) 2 R 3 , NR c3 S(0) 2 NR c3 R d3 , S(0)R b3 , S(0)NR c3 R d3 , S(0) 2 R b3 , or S(0) 2 NR c3 R d3 , wherein said C
  • R c and R D are each independently selected from H, halo, Q.e alkyl, C . 6 alkenyl, Ci-6 haloalkyl, CN, N0 2 , 0R a4 , SR a4 , C(0)R M , C(0)NR c4 R d4 , C(0)OR a4 , OC(0)R b4 , OC ⁇ NR ⁇ R" 4 , NR c4 R d4 , NR c4 C(0)R b4 , NR c4 C(0)OR a4 , NR c4 C(0)NR c4 R d4 , NR c4 S(0)R b4 , NR c4 S(0) 2 R b4 , NR c4 S(0) 2 NR c4 R d4 , S(0)R b4 , S(0)NR c4 R d4 , S(0)R b4 , S(0)NR c4 R d4 , S(0)R
  • each R Cy is independently selected from halo, Ci-6 alkyl, Ci-6 haloalkyl, C 2- 6 alkenyl, Ce-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO2, OR a5 , SR a5 , C(0)R b5 s C(0)NR c5 R d5 , C(0)OR a5 , OC(0)R b5 ; OC(0)NR c5 R d5 , NR c5 R d ⁇
  • Ci-e alkyl, C2-6 alkenyl Ce-io ryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci- ⁇ alkyl, CN, N0 2 , OR a5 , SR a5 , C(0)R b5 , C(0)NR c5 R dS , C(0)OR a5 ,
  • each R a , R a[ , R a2 , R 33 , R a4 , and R aS is independently selected from H, Ci- 6 alkyl, C1.4 haloalkyl, C2-6 alkenyl, Ce-io aryl, C3- 10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Gs-jo aryl-C 1 -4 alkyl, C3-io cycloalkyl-Ci.4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, or (4-10 membered heterocycloalkyl)-Ci-4 alkyl, wherein said Ci -6 alkyl, C2-6 alkenyl, C 6- to aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl- Ci-4 alkyi, C 3- io
  • each R bI , R b2 , R b3 , R b4 , and R bs is independently selected from H, C !-6 alkyl, C
  • haloalkyl C 2 . 6 alkenyl, C 6 -io aryl, C 3 -!o cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-io ryl-C M alkyl, Ca-te cycloalkyl-CM alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, or (4-10 membered heterocycloalky ⁇ -d ⁇ alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C 6 - 10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6 -io aryl- C 1-4 alkyl, C3-io cycloalkyl-CM alkyl, (5-10 membered heteroaryl) -C 1- alkyl, and (4-10 membered heterocycloalkyl)-Ci.
  • 4 alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C M alkyl, halo, CN, OR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR 6 , OC(0)R b6 , OC(0)NR c6 R d6 ) NR c6 R d6 ; NR c6 C(0)R b6 , NR c6 C(0)NR c6 R d6 ;
  • each R , R d , R cl , R dl , R° 2 , R d2 , R c3 , R d3 , R c4 , R d4 , R c5 , and R dS is independently selected from H, Ci-6 alkyl, CM haloalkyl, C2-6 alkenyl, C 6 -io aryl, C3-io cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-ioaryl-Ci-4 alkyl, C3-io cycloalkyl-Ci-4 alkyl, (5- 10 membered heteroaryl)-Ci-4 alkyl, or (4-10 membered heterocycloalkyl)-Ci-4 alkyl, wherein said Ci- 6 alkyl, C 2-6 alkenyl, Ce-toaryl, C3-10 cycloalkyl, 5-10 membered heteroaryl
  • 4 alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Ci- 4 alkyl, halo, CN, OR a6 ; SR a6 5 C(0)R b6 ⁇ C(0)NR c6 R d6 , C(0)OR a6 , OC(0)R b6 , OC(0)NR c6 R d6 , NR c6 R d6 ,
  • R c and R d together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6 -io aryl, 5-6 membered heteroaryl, halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR 6 R d6 , C(0)OR a6 , OC(0)R b6 , OC(0)NR c6 R d6 , NR c6 R d6 ; NR c6 C(0)R 6 , NR c C(0)NR c6 R dfi , NR c6 C(0)OR a6 , S(0)R b6 , S(0)NR c6 R d6 , S(0) 2 R b6 ⁇ NR
  • R c) and R dl together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci -6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6 -io aryl, 5-6 membered heteroaryl, halo, CN, OR 6 , SR a6 , C(0)R b6 , C(0)NR e6 R d5 , C(0)OR a6 , OC(0)R b6 , OC(0)NR c6 R d6 , NR c6 R d6 , NR cfi C(0)R 6 , NR c6 C(0)NR c6 R d6 5 NR c6 C(0)OR a6 , S(0)R b6 , S(0)NR c6 R d6 , S(0) 2 R b6 ,
  • R c2 and R d2 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6 -io aryl, and 5-6 membered heteroaryl, Ci-ehaloalkyl, halo, CN, OR a6 , SR a6 , C(0)R 6 ⁇ C(0)NR c6 R d6 , C(0)OR a6 , OC(0)R b6 , OC(0)NR c R d6 , NR c6 R d5 , NR c6 C(0)R b6 , NR c6 C(0)NR c6 R d6 ,
  • Ci-6 alkyl, 03 ⁇ 4 -7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, OR a6 , SR a5 , C(0)R b6 , C(0)NR c6 R d6 , C(O)0R a6 ,
  • R c3 and R d3 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, Ci ⁇ haloalkyl, halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 , OC(0)R b6 , OC(0)NR c6 R d6 , NR c6 R d6 , NR c6 C(0)R b6 , NR c6 C(0)NR c6 R d6 ,
  • Ci-6 alkyl, C3.7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, OR" 6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR af ⁇
  • R c4 and R d4 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from d-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, 5-6 membered heteroaiyl, Ci -6 haloalkyl, halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 , OC(0)R 6 , OC(0)NR c6 R d6 ; NR c6 R d6 , NR c6 C(0)R b6 , NR c6 C(0)NR c6 R d5 ⁇
  • cycloalkyl, 4-7 membered heterocycloalkyl, C 6 -io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 ,
  • R c5 and R d5 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ct-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6 -io aryl, 5-6 membered heteroaiyl, Ci-ehaloalkyl, halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR n5 , OC(0)R b6 , OC(0)NR c6 R d6 , NR c6 R d6 , NR c6 C(0)R b6 , NR c6 C(0)NR e6 R d6 ,
  • Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, OR a6 , SR a6 , C(0)R b6 , C(0)NR c6 R d6 , C(0)OR a6 ,
  • each R a6 , R b6 , R c6 , and R d6 is independently selected from H, CM alkyl, C2-4 alkenyl, C 3 . 7 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein said Ci-4 alkyl, C 2 .
  • 4 alkenyl, C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C alkyl, C1-4 alkoxy, CM alkylthio, C alkylamino, and di(Ci-4 alkyl)amino;
  • n 1 or 2;
  • p is 1 , 2, or 3;
  • q 1 or 2;
  • any aforementioned 4-10 or 4-7 membered heterocycloalkyl group optionally comprises 1, 2, or 3 oxo substituents, wherein each oxo substituent that is present is substituted on a ring-forming carbon, nitrogen, or sulfur atom of the 4-10 or 4-7 membered heterocycloalkyl group.
  • L is O.
  • L is NR 4 ,
  • W is CR 5 ; X is N; and Y is CR 7 .
  • W is N; X is N; and Y is CR 7 ,
  • W is CR 5 ; X is CR 6 ; and Y is N.
  • W is CR 5 ;
  • X is CR 6 ; and
  • Y is CR 7 .
  • W is N; X is CR 6 ; and Y is CR 7 ,
  • R 2 is H and R 3 is H.
  • R 2 is H and R 3 is C alkyl
  • R 2 is H and R 3 is methyl.
  • R 2 is H and R 3 is C]-4 haloalkyl.
  • R 2 is H and R 3 is trifluoromethyl.
  • n 2
  • R 1 is H.
  • R 1 is Ci-io alkyl, Qj-io cycloalkyl, phenyl, -(CR 8 R 9 ) P OC(0)R 10 , -(CR 8 R 9 )p NR l l R' 2 , or -(CR 8 R 9 ) p C(0)NR n R 12 , wherein said CMO alkyl, C 3 -io cycloalkyl, and phenyl are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from F, CI, Br, CN, CM alkyl, and Ci-4 haloalkyl.
  • R 1 is Ci-io alkyl.
  • R 1 is ethyl
  • R 4 is H.
  • R 5 is H.
  • R 6 is H.
  • R 7 is other than H.
  • R 7 is C alkyl, NR ,3 R ⁇ or OR 15
  • R 7 is NR t3 R H .
  • R 7 is NH 2 .
  • R 7 is CM alkyl. In some embodiments, R 7 is OR 15 .
  • Ring A is C3-iocycloalkyl.
  • Ring A is Ce-io aryl.
  • Ring A is phenyl
  • Ring A is 4 to 10-membered heterocycloalkyl.
  • Ring A is phenyl, adamantanyl, naphthyl, 1,2,3,4- tetrahydroquinoxalinyl, 3,4-dihydroqinazolinyl, 1,2,3,4-tetrahydiOquinazolinyl, or pyridyl.
  • Ring A is 5 to 10-membered heteroaryl
  • At least one of R A , R B , R c , and R D is other than hydrogen.
  • At least two of R A , R B , R c , and R D are other than hydrogen.
  • R A is Cy 1 .
  • R A is Ce-io aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R Cy .
  • R A is 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R Cy .
  • R A is 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from R Cy .
  • R A is pyrazolyl which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R Cy .
  • R A is 3 -methyl- lH-pyrazol-1 -yl.
  • R A is C 6 -toaryl optionally substituted by 1, 2, or 3 substituents independently selected from R Cy .
  • R A is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from R Cy .
  • R B is H.
  • R B is Cy 2 , halo, Ci -6 alkyl, C 2 -6 alkenyl, Ci-6 haloalkyl, CN, N0 2 , OR e3 , SR 33 , C(0)R b3 , C(0)NR c3 R d3 ; C(0)OR a3 , OC(0)R b3 , OC(0)NR c3 R d3 , NR c3 R d3 ,
  • R B is Cy 2 .
  • R B is C 6 -io aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1 , 2, 3, 4, or 5 substituents independently selected from R Cy .
  • R B is halo, Ci-e alkyl, C 2- 6 alkenyl, O-e haloalkyl, CN, N0 2 , OR a3 , SR* 3 , C(0)R b3 , C(0)NR c3 R d3 , C(0)OR a3 , OC(0)R b3 , OC(0)NR c3 R d3 , NR c3 R d3 , NR c3 C(0)R b3 , NR ⁇ C-JOR 33 , NR c3 C(0)NR c3 R d3 , NR c3 S(0)R b3 , NR c3 S(0) 2 R b3 , NR c3 S(0) 2 R b3 5 NR c3 S(0) 2 NR c3 R d3 , S(0)R b3 , S(0)NR o3 R d3 , S(0) 2 R 3 , and S(0) 2 NR c3 R d3 ,
  • 6 alkyl and C 2 . 6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 2 , halo, Ci- 6 alkyl, C 2 . 6 alkenyl, Ci_ 6 haloalkyl, CN, N0 2j OR 33 , SR a3 , C(0)R b3 , C(0)NR c3 R d3 , CCC OR* 3 , OC(0)R 3 , OC(0)NR c3 R d3 , NR c3 R d3 , NR c3 C(0)R b3 , NR c3 C(0)OR a3 , NR c3 C(0)NR c3 R d3 5
  • R B is halo
  • R c is H.
  • R c is halo, Ci-c alkyl, C 2-6 alkenyl, Ci-6 haloalkyl, CN, N0 2 , OR 4 , SR a4 , C(0)R b4 > C(0)NR c4 R d4 , C(0)OR a4 , OC(0)R b4 , OC(0)NR c4 R d4 , NR ⁇ R ⁇ , NR c C(0)R b4 ) NR c4 C(0)OR a4 , N ⁇ C NR ⁇ 4 , NR c4 S(0)R b4 , NR c S(0) 2 R b ) NR c S(0) 2 NR c R d4 , S(0)R b4 , S(0)NR c4 R d4 , S(0) 2 R M , and S(0) 2 NR c4 R d4 ; wherein said Ci -6 aikyl and C 2-6 alkenyl are each optionally substituted
  • R D is H
  • R D is halo, Ci- 6 alkyi, C 2 . 6 alkenyl, Cj-6 haloalkyl, CN, N0 2 , OR a4 , SR a4 , C(0)R b4 , C(0)NR c4 R d4 , C(0)OR n4 5 OC(0)R b4 , OC(0)NR c4 R d4 , NR ⁇ R 114 , NR c C(0)R b4 J NR c4 C(0)OR a4 , NR c C(0)NR c R d4 , NR c4 S(0)R b4 , NR c4 S(0) 2 R b4 , NR o4 S(0) 2 NR c4 R d4 , S(0)R b4 , S(0)NR c4 R d4 , S(0) 2 R b4 , and S(0) 2 NR c4 R d4 ; wherein said Ci-6 alkyi and
  • 6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 6 .io aryl, C 3- io cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, Ci-6 alkyl, C 2 - 6 alkenyl, Ci- 6 haloalkyl, CN, N0 2 , OR a4 , SR a4 , C(0)R b4 , C(0)NR c4 R d4 , C(0)OR a4 , OC(0)R 4 , OC(0)NR c4 R d 5 NR ⁇ R* 14 , NR c4 C(0)R 4 , NR c C(0)OR a4 , NR c C(0)NR c R d4 , NR c S(0 ⁇ R M , NR ⁇ O) ⁇ 4 , NR c4 S(0) 2 NR c R d4 , S(0)R b
  • the compounds of the invention have Formula lib:
  • the compounds of the invention have Formula lie: He.
  • L is NR4.
  • R 3 is H.
  • R 2 is CF 3 and R 3 is H.
  • R ! is H or Ci-io alkyl.
  • R A is Cy 1 .
  • R A is C6-io aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1 , 2, 3, 4, or 5 substituents independently selected from R Cy .
  • R A is 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R Cy .
  • R A is 5 to 6-membered heteroaryl optionally substituted by 1 , 2, or 3 substituents independently selected from R Cy .
  • R A is Ce-io aryl optionally substituted by 1, 2, or 3 substituents independently selected from R Cy
  • R A is phenyl optionally substituted by 1 , 2, or 3 substituents independently selected from R Cy .
  • R B is Cy 2 .
  • R B is H, halo, Ci-e alkyl, C 2 -6 alkenyl, C 1-6 haloalkyl, CN, OR a3 , C(0)NR c3 R d3 5 or C(0)OR a3 , wherein said Ci.
  • 6 alkyl and C 2 - 6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci-6 haloalkyl, CN, N0 2; OR 33 , SR 83 , C(0)R b3 , C(0)NR c3 R d3 , C(0)OR a3 , OC(0)R b3 , OC(0)NR c3 R d3 ; NR c3 R d3 5 NR c3 C(0)R b3 , NR c3 C(0)OR a3 ⁇ NR c3 C(0)NR c3 R d3 , NR c3 S(0)R b3 , NR cl S(0) 2 R b3 , NR c3 S(0) 2 NR c3 R d3 , S(0)R b3 , S(0)NR c3 R d3 , S(0)R b3 , and S(0) 2 NR c3 R d3 .
  • R c is H.
  • R D is H.
  • R 5 is H.
  • R 6 is H
  • the compounds of the invention have Formula Ilia or Ilib:
  • R 2 is CF 3 .
  • R 1 is H or Ci-io alkyl.
  • R A is Cy'
  • R A is C 6 -ioaryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R Cy .
  • R A is 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R Cy .
  • R A is 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from R Cy .
  • R A is Ce-io ryl optionally substituted by 1, 2, or 3 substituents independently selected from R Cy .
  • R A is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from R Cy .
  • R B is Cy 2 . In some embodiments, where the compounds of the invention have Formula Ilia or Illb, R B is H, halo, Ci. 6 alkyl, C 2 -6 alkenyl, Ci-e haloalkyl, CN, OR a3 ; C(0)NR c R d3 ⁇ or C(0)OR a3 , wherein said C] -6 alkyl and C 2 -6 alkenyl are each optionally substituted with 1, 2, or 3
  • R c is H.
  • R D is H.
  • the compounds of the invention have Formula IV:
  • R 2 is
  • R 1 is H or Ci-io alkyl.
  • R A is Cy 1 .
  • R A is C 6 - lo ryi or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R Cy , In some embodiments, where the compounds of the invention have Formula IV, R A is 5- 10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R Cy ,
  • R A is 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from R c >'.
  • R A is Ce- lo aryl optionally substituted by 1, 2, or 3 substituents independently selected from R Cy .
  • R A is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from R Cy .
  • R B is
  • R Q is H, halo, Ct-6 alkyl, C2-6 alkenyl, Cue haloalkyl, CN, OR* 3 , C(0)NR c3 R d3 , or C(0)OR a3 , wherein said Ci -6 alkyl and C 2 - 6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci-6 haloalkyl, CN, N0 2 , OR a3 , SR a3 , C(0)R b3 , C(0)NR c3 R d3 , C(0)OR a3 , OC(0)R b3 , OC(0)NR c3 R d3 , NR c3 R d3 , NR c3 C(0)R b3 , NR c3 C(0)OR a3 ,
  • R c is H
  • R D is H
  • the compounds of the invention have Formula Va:
  • R 2 is
  • R 1 is H or Ci-io alkyl.
  • R A is
  • R A is C 6 - loaryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R Cy .
  • R A is 5- 10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R Cy ,
  • R A is 5 to 6-membered heteroaryl optionally substituted by 1 , 2, or 3 substituents independently selected from R C
  • R A is C 6 - lo aryl optionally substituted by 1 , 2, or 3 substituents independently selected from R Cy .
  • R A is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from R Cy .
  • R B is
  • R B is H, halo, Ci-6 alkyl, C 2 . 6 alkenyl, C J-6 haloalkyl, CN, OR a3 , C(0)NR c3 R d3 , or C(0)OR fl3 , wherein said Ci-6 alkyl and C 2 .
  • 6 alkenyl are each optionally substituted with 1 , 2, or 3 substituents independently selected from halo, Ci -6 haloalkyl, CN, N0 2; OR a3 , SR a3 , C(0)R 3 , C(0)NR c3 R d3 5 C(0)OR a3 , OC(0)R b3 , OC(0)NR c3 R d3 , NR c3 R d3 , NR c3 C(0)R b3 , R ⁇ C ⁇ OR 83 ,
  • the compounds of the invention have Formula Vb:
  • R 2 is
  • R ! is H or Ci-io alkyl.
  • R A is
  • R A is C 6 - io aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1 , 2, 3, 4, or 5 substituents independently selected from R Cy .
  • R A is 5- 10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R ⁇ ' .
  • R A is 5 to 6-membered heteroaryl optionally substituted by 1 , 2, or 3 substituents independently selected from R Cy .
  • R A is C 6 - io aryl optionally substituted by 1, 2, or 3 substituents independently selected from
  • R A is phenyl optionally substituted by 1 , 2, or 3 substituents independently selected from
  • R B is
  • R B is H, halo, Ci-6 alkyl, C 2 . 6 alkenyl, Ci- 6 haloalkyl, CN ; OR a3 , C(0)NR e3 R d3 , or C(0)OR a3 , wherein said Ci-6 alkyl and C 2 .
  • 6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci-e haloalkyl, CN, N0 2 , OR a3 , SR a3 , C(0)R b3 , C(0)NR c3 R d3 , C(0)OR a3 , OC(0)R w , OC(0)NR c3 R d3 , NR c3 R d3 , NR c3 C(0)R b3 , NR e3 C(0)OR a3 ,
  • the compounds of the invention have Formula VI:
  • R 2 is
  • R 1 is II or Ci-to alkyl.
  • R B is
  • Cy 2 is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from R Cy .
  • R B is H, halo, Ci-6 alkyl, C 2 -6 alkenyl, Ci -6 haloalkyl, CN, OR a3 , C(0)NR c3 R d3 , or C(0)OR a3 , wherein said Ci-6 alkyl and C 2 .
  • 6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci- 6 haloalkyl, CN, N0 2> OR a3 , SR a3 , C(0)R b ⁇ C(0)NR c3 R d3 ⁇ C(0)OR a3 , OC(0)R b3 ; OC(0)NR c3 R d3 , NR c3 R d3 , NR c3 C(0)R b3 , NR c3 C(0)OR a3 ,
  • R c is H
  • R D is H
  • the compounds of the invention have Formula VIA:
  • R 2 is
  • R 1 is H or Cj-io alkyl.
  • R B is
  • Cy 2 is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from R Cy ,
  • R B is H, halo, Ci -6 alkyl, C 2 . 6 alkenyl, Ci- 6 haloalkyl, CN, OR 83 , C(0)NR c3 R d ⁇ or C(0)OR a3 , wherein said Ci-6 alkyl and C 2- 6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci -6 haloalkyl, CN, N0 2 , OR a3 , SR a3 , C(0)R b3 , C(0)NR c3 R d3 , C(0)OR a3 , OC(0)R b3 , OC(0)NR c3 R d3 , NR o3 R d3 , NR e3 C(0)R b3 ⁇ NR c3 C(0)OR a3 , NR c3 C(0)NR c3 R d3 , NR
  • the compounds of the invention have Formula VII:
  • a is 0, 1, 2, or 3.
  • R 2 is
  • R ! is H or Ci-io alkyl.
  • R B is
  • R B is H, halo, Ci-6 alk l, C 2-6 alkenyl, Ci-6 haloalkyl, CN, OR a3 , C(0)NR c3 R ⁇ t3 , or C(0)OR a3 , wherein said Ci-6 alkyl and C 2 . 6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C
  • R B is H or halo. In some embodiments, where the compounds of the invention have Formula VII, R B is halo.
  • R c is H.
  • R D is H.
  • R Cy is halo, Ci-6 alkyl, Ci- 6 haloalkyl, 4-10 membered heterocycloalkyl, CN, N0 2) OR aS , SR aS , C(0)R b5 , C(0)NR c5 R d5 , C(0)OR aS , NR cS R ds , S(0) 2 R b5 , and S(0) 2 NR c5 R d5 , wherein said Ci -6 alkyl and 4- 10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci- 6 alkyl, CN, N0 2 , OR a5 , SR a5 , C(0)R b5 , C(0)NR c5 R dS , C(0)OR a5 , OC(0)R b5 , OC(0)NR c5 R d5 ,
  • a is 0, 1, 2, or 3.
  • R 2 is
  • R 1 is H or Ci-io alkyl.
  • R B is
  • R B is H, halo, Ci-6 alkyl, C 2 . 6 alkenyl, Ci -6 haioalkyl, CN, OR a3 , C(0)NR c3 R d3 , or C(0)OR a3 , wherein said C].
  • 6 alkyl and C 2 . 6 alkenyl are each optionally substituted with 1 , 2, or 3 substituents independently selected from halo, Ci.
  • R B is H or halo.
  • R B is halo
  • R c is
  • R D is H
  • R Cy is halo, Ci -6 alkyl, Ci-e haioalkyl, 4-10 membered heterocycloalkyl, CN, N0 2 , OR 85 , SR a5 , C(0)R b5 , C(0)NR cS R d5 , C(0)OR aS , NR c5 R d5 ( S(0) 2 R bS , and S(0) 2 NR c5 R d5 , wherein said Ct-6 alkyl and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, CN, N0 2 , OR" 5 , SR a5 , C(0)R b5 , C(0)NR cS R ds , C(0)OR a5 , OC(0)R b5 , OC(0)NR cS R ds ,
  • a is 0.
  • the chiral carbon to which -C(0)OR' is attached has an S configuration.
  • the carbon to which -R 2 is attached is chiral and has an R configuration.
  • substituted means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group.
  • the hydrogen atom is formally removed and replaced by a substituent.
  • a single divalent substituent e.g., oxo
  • optionally substituted means unsubstituted or substituted.
  • the substituents are independently selected, and substitution may be at any chemically accessible position. It is to be understood that substitution at a given atom is limited by valency.
  • the term "Ci-j" indicates a range which includes the endpoints, wherein i and j are integers and indicate the number of carbons, Examples include CM, Ci-6, and the like.
  • n-membered where n is an integer typically describes the number of ring- forming atoms in a moiety where the number of ring-forming atoms is n.
  • piperidinyl is an example of a 6-membered heterocycloalkyl ring
  • pyrazoiyl is an example of a 5- membered heteroaryl ring
  • pyridyl is an example of a 6-membered heteroaryl ring
  • 1, 2, 3, 4- tetrahydro-naphthalene is an example of a 10-membered cycioalkyl group.
  • aryl, heteroaryl, cycioalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency.
  • a pyridine ring or “pyridinyl” may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.
  • each variable can be a different moiety independently selected from the group defining the variable.
  • the two R groups can represent different moieties independently selected from the group defined for R,
  • Cj-j alkyl refers to a saturated hydrocarbon group that may be straight-chain or branched, having i to j carbon atoms.
  • the alkyl group contains from 1 to 10, 1 to 6, 1 to 4, or from 1 to 3 carbon atoms.
  • alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, and t-butyl.
  • Ci-j alkoxy refers to a group of formula -O-alkyl, wherein the alkyl group has i to j carbon atoms,
  • Example alkoxy groups include methoxy, ethoxy, and propoxy (e.g., n-propoxy and isopropoxy).
  • the alkyl group has 1 to 3 carbon atoms or 1 to 4 carbon atoms.
  • Ci-j alkenyl refers to an alkyl group having one or more double carbon- carbon bonds and having i to j carbon atoms. In some embodiments, the alkenyl moiety contains 2 to 6 or to 2 to 4 carbon atoms.
  • Example alkenyl groups include, but are not limited to, ethenyl, /7-propenyl, isopropenyl, w-butenyl, seobutenyl, and the like.
  • Ci-j alkylamino refers to a group of formula -NH(alkyl), wherein the alkyl group has i to j carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • di-Ci-j-alkylamino refers to a group of formula -N(alkyl) 2j wherein the two alkyl groups each has, independently, i to j carbon atoms.
  • each alkyl group independently has 1 to 6 or 1 to 4 carbon atoms.
  • thio refers to a group of formula -SH.
  • Cj.j alkylthio refers to a group of formula -S-alkyl, wherein the alkyl group has ⁇ to j carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • amino refers to a group of formula -NH 2 .
  • Cj.j aryl refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbon having i to j ring-forming carbon atoms, such as, but not limited to, phenyl, 1-naphthyl, 2- naphthyl, anthracenyl, phenanthrenyl, and the like.
  • aryl is C 6 -io aryl.
  • the aryl group is a naphthalene ring or phenyl ring.
  • the aryl group is phenyl.
  • arylalkyl refers to a group of formula -Ci-j alkyl— (Cj.j aryl). In some embodiments, arylalkyl is C 6 -io atyl-Ci-3 alkyl. In some embodiments, arylalkyl is C 6 -io aryl-Ci-4 alkyl. In some embodiments, arylalkyl is benzyl.
  • Cycloalkyl refers to a non-aromatic cyclic hydrocarbon moiety having i to j ring-forming carbon atoms, which may optionally contain one or more alkenylene groups as part of the ring structure.
  • Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems.
  • cycloalkyl moieties that have one or more aromatic rings (aryl or heteroaryl) fused to the cycloalkyl ring, for example, benzo or pyrido derivatives of cyclopentane, cyclopentene, cyclohexane, and the like.
  • the cycloalkyl group includes a fused aromatic ring
  • the cycloalkyl group can be attached at either an atom in the aromatic or non-aromatic portion.
  • One or more ring-forming carbon atoms of a cycloalkyl group can be oxidized to form carbonyl linkages.
  • cycloalkyl is C3-10 or C3-7 cycloalkyl, which can be monocyclic or polycyclic.
  • exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyi, adamantanyl and the like.
  • the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • cycloalkylalkyl refers to a group of formula -Cj.j alkyl— (Ci-j cycloalkyl). In some embodiments, cycloalkylalkyl is C3-7 cycloalkyl-Ci-3 alkyl, wherein the cycloalkyl portion is monocyclic. In some embodiments, cycloalkylalkyl is C3-7 cycloalkyl-Ci-4 alkyl.
  • Ci-j haloalkoxy refers to a group of formula -O-haloalkyl having i to j carbon atoms.
  • An example haloalkoxy group is OCF3.
  • An additional example haloalkoxy group is OCHF 2 .
  • the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • halo refers to a halogen atom selected from F, CI, I or Br. In some embodiments, “halo” refers to a halogen atom selected from F, CI, or Br. In some embodiments, the halo group is F,
  • Ci-j haloalkyl refers to an alkyl group having from one halogen atom to 2s+l halogen atoms which may be the same or different, where "s" is the number of carbon atoms in the alkyl group, wherein the alkyl group has i to j carbon atoms.
  • the haloalkyl group is fluoromethyl, difluoromethyl, or trifluoromethyl. In some embodiments, the haloalkyl group is trifluoromethyl. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • heteroaryl refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic moiety, having one or more heteroatom ring members selected from nitrogen, sulfur and oxygen.
  • the heteroaryl group is a 5- to 10-membered heteroaryl ring, which is monocyclic or bicyclic and which has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • the heteroaryl group is a 5- to 6-membered heteroaryl ring, which is monocyclic and which has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • heteroaryl group When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different.
  • the nitrogen atoms in the ring(s) of the heteroaryl group can be oxidized to form N-oxides.
  • Example heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, azolyl, oxazole, thiazole, imidazole, furan, thiophene, quinoline, isoquinoline, indole, benzothiophene, benzofuran, benzisoxazole, imidazo[l ,2-Z>]thiazole, purine, and the like.
  • a 5-membered heteroaryl is a heteroaryl group having five ring-forming atoms comprising carbon and one or more ⁇ e.g., 1, 2, or 3) ring atoms independently selected from N, 0, and S.
  • Example five-membered heteroaryls include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3- thiadiazolyl, 1 ,2,3-oxadiazolyl, 1,2,4-triazolyl, 1 ,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4- triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.
  • a six-membered heteroaryl is a heteroaryl group having six ring-forming atoms wherein one or more ⁇ e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S.
  • Example six-membered heteroaryls include pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.
  • heteroarylalkyl refers to a group of formula -Ci-j alkyl-
  • heteroaryi (heteroaryi).
  • heteroarylalkyl 5-10 membered alkyl, wherein the heteroaryl portion is monocyclic or bicyclic and lias 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • the heteroarylalkyl is 5-6 membered heteteiOaryl-Ci-3 alkyl or 5-6 membered heteteroaryl-Ci.4 alkyl, wherein the heteroaryl portion is monocyclic and has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • heterocycloalkyl refers to a non-aromatic ring or ring system, which optionally contains one or more alkenylene groups as part of the ring structure, and which has at least one heteroatom ring member independently selected from nitrogen, sulfur and oxygen.
  • heterocycloalkyl groups contains more than one heteroatom, the heteroatoms may be the same or different.
  • Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems, including spiro systems.
  • heterocycloalkyl moieties that have one or more aromatic rings (aryl or heteroaryl) fused to the non-aromatic ring, for example, 1,2,3,4-tetrahydro-quinoline, dihydrobenzofuran and the like.
  • heterocycloalkyl group includes a fused aromatic ring, the heterocycloalkyl group can be attached at either an atom in the aromatic or non-aromatic portion.
  • the carbon atoms or heteroatoms in the ring(s) of the heterocycloalkyl group can be oxidized (e.g. have one or two oxo substituents) to form a carbonyl, or sulfonyl group (or other oxidized linkage) or a nitrogen atom can be quaternized.
  • the heterocycloalkyl group is 5- to 10- membered, which can be monocyclic or bicyclic and which has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • the heterocycloalkyl group is 5- to 6-membered or 5- to 7-membered
  • heterocycloalkyl groups include 1, 2, 3, 4-tetrahydroquinoline, dihydrobenzofuran, azetidine, azepane,
  • heterocycloalkyl groups include 2-oxotetrahydrofuranyl, 2-oxopyrrolidinyl, 2-oxoimidazolidinyI, 1 -oxo-1 ,2,3 ⁇ 4-tetrahydiOisoquinolin-6-yl, and 2-oxo-l ,3-dioxolan-4-yl.
  • heterocycloalkylalkyl refers to a group of formula -Ci-j aikyl- (heterocycloalkyl). In some embodiments, heterocycloalkylalkyl is 5-10 membered
  • heterocycloalkyl portion is monocyclic or bicyclic and has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • heterocycloalkylalkyl is 5-6 membered heterocycloalkyl-Ci -4 alkyl wherein the heterocycloalkyl portion is monocyclic and has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereoisomers, are intended unless otherwise indicated.
  • An example method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid.
  • Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as ⁇ -camphorsulfonic acid.
  • resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of -methylbenzylamine (e.g., S and R forms, or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine,
  • Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine).
  • an optically active resolving agent e.g., dinitrobenzoylphenylglycine
  • Suitable elution solvent composition can be determined by one skilled in the art.
  • Tautomeric forms result from the swapping of a single bond with an adj cent double bond together with the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1, 2, 4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole.
  • Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds, isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • compound is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted.
  • Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.
  • Compounds herein identified by name or structure without specifying the particular configuration of a stereocenter are meant to encompass all the possible configurations at the stereocenter, For example, if a particular stereocenter in a compound of the invention could be R or S, but the name or structure of the compound does not designate which it is, than the stereocenter can be either R or S.
  • Ail compounds, and pharmaceutically acceptable salts thereof can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated.
  • the compounds of the invention, or salts thereof are substantially isolated.
  • substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected.
  • Partial separation can include, for example, a composition enriched in the compounds of the invention, Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • ambient temperature and “room temperature,” as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a
  • the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, EtOAc, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrate (CH3CN) are preferred.
  • non-aqueous media like ether, EtOAc, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrate (CH3CN) are preferred.
  • suitable salts are found in Remington's Pharmaceutical Sciences, 17 th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et a!., J. Pharm. Sci,, 1977, 66(1), 1-19, and in Stahl et al, Handbook of Pharmaceutical Salts: Properties, Selection
  • reaction progress may be monitored by thin layer chromatography (TLC) or
  • step 1 an alcohol (where the ring substituted by R A , R B , R c , R D corresponds to ring A of
  • Formula I) (see, e.g., Intermediate 1) in dioxane is treated with a dichloro heterocycle (e.g., 2- amino-4 J 6-dichloropyrimidine) in the presence of a base (e.g., Cs2C0 3 ), and heated for several hours (e.g. 12-24 h) at reflux.
  • a spirocycle of formula B e.g., (S)-2-benzyl 3-ethyl 2,8- diazaspii [4.5]decane-2,3-dicarboxylate
  • a solvent e.g., dioxane
  • step 3 the amino protecting group (P) (e.g. CBZ or BOC) of a compound of formula C is removed (e.g. with TMSI, transition metal-catalyzed hydro genation, or strong acid depending on the nature of the protecting group).
  • step 4 a compound of formula D is obtained by ester hydrolysis (e.g. with LiOH in aqueous THF). In some instances, the sequence of steps 3 and 4 can be reversed.
  • Scheme 1 Alcohols (e.g., Intermediate 1) used in Scheme 1 can be prepared as shown in Scheme 2.
  • step 1 to a solution of base (e.g. potassium f-butoxide) in a solvent (e.g. DMSO) is added 3 -methyl pyrazole and an aryl bromide E (e.g., l,4-dibromo-2-fluoiObenzene), and the mixture is heated for several hours (e.g.
  • base e.g. potassium f-butoxide
  • solvent e.g. DMSO
  • a compound of formula F is treated with a a Grignard reagent (e.g., -PrMgCl) in a solvent (e.g., THF), then reacted with ethyl trifluoroacetate in a solvent (e.g., THF) to provide a ketone of formula G.
  • a a Grignard reagent e.g., -PrMgCl
  • a solvent e.g., THF
  • ethyl trifluoroacetate e.g., THF
  • a ketone of formula G can be obtained by treating first a fluoro aromatic compound of formula El with a strong base (e.g., LDA), then trapping the intermediate aryl lithium with trifluoroacetic acid ethyl ester to give a compound of formula Fl (Step l ).
  • a strong base e.g., LDA
  • 3 -methyl pyrazole can be introduced onto a ketone of formula Flvia an
  • a ketone of formula G is converted stereospecifically into a chiral alcohol of formula H via either chiral transfer hydrogenation (e.g., with potassium formate) in the presence of a transition metal catalyst (e.g., pentamethyl cyclopentadienyl iridium (III) chloride dimer) and a chiral ligand (e.g., (lR,2R)-(-)-N-(4-toluene sulfonyl)-l,2-diphenyl ethylene diamine) in a solvent (e.g., acetonitrile), or alternatively with a faorane reagent (e.g.
  • a transition metal catalyst e.g., pentamethyl cyclopentadienyl iridium (III) chloride dimer
  • a chiral ligand e.g., (lR,2R)-(-)-N-(4-toluene s
  • an alcohol of formula K can be made in a similar fashion starting from a ketone of formula J (step 2c).
  • a ketone of formula J can be prepared in one step (step 2c) by reacting the aryl ester of formula E2 with a nucleophilic silylating agent (e.g., trimethyl(trifluoromethyi)silane) in the presence of a fluoride source (e.g., TBAF) in an inert solvent (e.g., THF).
  • a nucleophilic silylating agent e.g., trimethyl(trifluoromethyi)silane
  • step 1 to a spirocyclic compound of B (e.g., (S)-2-benzyl 3-ethyl 2,8- diazaspiro[4.5]decane-2,3-dicarboxylate) in dioxane is added a di-halo heterocycle (e.g., 2- amino-4,6-dichloi pyrimidine) in the presence of a base (e.g., Cs 2 C0 3 ) under solvent reflux (e.g., dioxane) to provide a compound of formula M.
  • B e.g., (S)-2-benzyl 3-ethyl 2,8- diazaspiro[4.5]decane-2,3-dicarboxylate
  • a di-halo heterocycle e.g., 2- amino-4,6-dichloi pyrimidine
  • a base e.g., Cs 2 C0 3
  • solvent reflux e.g., dioxane
  • step 2 to a compound of formula M in a solvent (e.g., dioxane) is added an alcohol or an amine of formula O (e.g., Intermediate 7 or 16) in the presence of a base (e.g., Cs C03). After heating at reflux for several hours (e.g., 12-24 h), a compound of formula P is obtained.
  • step 3 the amino protecting group (P) (e.g., CBZ or BOC) of a compound of formula P is removed (e.g., with TMSI, transition metal-catalyzed hydrogenation, or acid).
  • step 4 a compound of formula Q is obtained by ester hydrolysis (e.g., with LiOH in aqueous THF).
  • the sequence of steps 3 and 4 can be reversed.
  • step 1 to a compound of formula R in a solvent (e.g., aqueous dioxane) is added a boronic acid or boronate (e.g., phenyl boronic acid) in the presence of a palladium catalyst (e.g., PdCla(dppf)- CH2CI2) and a base (e.g., KHCO3), and the mixture heated to reflux for several hours (e.g., 12- 24) to provide a compound of formula S.
  • a solvent e.g., aqueous dioxane
  • a boronic acid or boronate e.g., phenyl boronic acid
  • a palladium catalyst e.g., PdCla(dppf)- CH2CI2
  • base e.g., KHCO3
  • step 3 the amino protecting group (P) (e.g., CBZ or BOC) of a compound of formula S is removed (e.g., with TMSI, transition metal-catalyzed hydrogenation, or acid).
  • step 4 a compound of formula T is obtained by ester hydrolysis (e.g., with LiOH in aqueous THF).
  • step 4 the sequence of steps 2 and 3 can be reversed.
  • a similar set of conditions can be used when starting with a compound of formula U or X, to obtain a compound of formula W or AA, respectively (Schemes 4b and 4c).
  • step 1 Various substitutions of the central 6-membered ring (e.g., the ring containing W, X, and Y) can be accomplished as shown in Scheme 5.
  • step 1 to a solution of a methyl sulfide of formula AB in an inert solvent (e.g., CH 2 C1 2 ) is added an oxidant (e.g., m-CPBA).
  • an oxidant e.g., m-CPBA
  • the solution is stirred at RT for several hours (e.g., 12-24 h) to provide a sulfone of formula AC.
  • step 2 to a solution of a compound of formula AC in a solvent (e.g., dioxane) is added a spirocyclic compound of formula B (e.g., (S) ⁇ 2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3- dicarboxylate) in the presence of a base (e.g., CS2CO3), and the mixture is heated for several hours (e.g., 12-24 h) to provide a sulfone of formula AD.
  • the ester group is saponified (e.g., with LiOH) in an aqueous or alcoholic solvent (e.g., aqueous THF) to provide an acid of formula AE.
  • a solvent e.g., dioxane
  • a spirocyclic compound of formula B e.g., (S) ⁇ 2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane
  • step 4 heating an acid of formula AE in the presence of an alcohol or an amine (e.g., phenol) and a base (e.g., Cs 2 C0 3 ) for several hours (e.g., 16-24 h) in a solvent (e.g., dioxane), followed in step 5 by deprotection of the amine (e.g. with TMSI, transition metal- catalyzed hydrogenation, or acid) provides a compound of formula AF.
  • an alcohol or an amine e.g., phenol
  • a base e.g., Cs 2 C0 3
  • a solvent e.g., dioxane
  • Ester group substituents can be introduced by the general method of Scheme 6. Briefly, in step 1, to a solution of an acid of formula AG in an inert solvent (e.g., CH 2 C1 2 ) is added a coupling reagent (e.g., EDCI and DMAP), followed by an alcohol (e.g., propanol) to provide a compound of formula AH. In step 2, the benzyl groups of the benzyl ester and of the N-CBZ group can be removed with reagents such as TMSI or by transition metal-catalyzed
  • an inert solvent e.g., CH 2 C1 2
  • a coupling reagent e.g., EDCI and DMAP
  • an alcohol e.g., propanol
  • Ethyl esters can be generally prepared according to Scheme 7, Briefly, deprotection of the amino group in a compound of formula AJ, can be accomplished either with the use of a dealkylating agent (e.g., TMSI) or via transition metal-catalyzed hydrogenation (e.g., H 2 with Pd/C) if the protecting group is CBZ, or with a strong acid (e.g., TFA or HCl), if the protecting group is BOC, to provide AK.
  • a dealkylating agent e.g., TMSI
  • transition metal-catalyzed hydrogenation e.g., H 2 with Pd/C
  • a strong acid e.g., TFA or HCl
  • an amino acid of formula AL is dissolved in an alcoholic solvent (e.g., n-octanol), optionally in the presence of a co-solvent (e.g., toluene), and heated in the presence of acid (e.g., p-TSA) for several hours (e.g., 12-24 h), optionally in the presence of a water trapping material (e.g., molecular sieve) or apparatus (e.g., Dean-Stark trap) to produce an ester of formula AM.
  • an alcoholic solvent e.g., n-octanol
  • a co-solvent e.g., toluene
  • acid e.g., p-TSA
  • an acid of formula AN is dissolved in a solvent (e.g., DMF) in the presence of a base (e.g., K2CO3) and treated with an alkyl halide (e.g., 2-chloro-ethyl-dimethyl-amine). After heating the solution for several hours (e.g., 12-24 h), an ester of formula AO is obtained.
  • a solvent e.g., DMF
  • a base e.g., K2CO3
  • an alkyl halide e.g., 2-chloro-ethyl-dimethyl-amine
  • /-Butyl esters can be made via direct alcohol coupling to the acid, as shown in Scheme 10.
  • a solvent e.g., DMF
  • a coupling agent e.g., EDCI and DMAP
  • step 2 removal of the amino protecting group is achieved as described earlier to afford a compound of formula AS.
  • the compounds of the invention can be used to inhibit the activity of the TPH1 enzyme in a cell by contacting the cell with an inhibiting amount of a compound of the invention.
  • the cell can be part of the tissue of a living organism, or can be in culture, or isolated from a living organism. Additionally, the compounds of the invention can be used to inhibit the activity of the TPH1 enzyme in an animal, individual, or patient, by administering an inhibiting amount of a compound of the invention to the cell, animal, individual, or patient.
  • Compounds of the invention can also lower peripheral serotonin levels in an animal, individual, or patient, by administering an effective amount of a compound of the invention to the animal, individual, or patient.
  • the compounds of the invention can lower levels of peripheral serotonin (e.g., 5-HT in the GI tract) selectively over non-peripheral serotonin (e.g., 5-HT in the CNS).
  • the selectivity is 2-fold or more, 3- fold or more, 5-fold or more, 10-fold or more, 50-fold or more, or 100-fold or more.
  • the compounds of the invention are useful in the treatment and prevention of various diseases associated with abnormal expression or activity of the TPH1 enzyme, or diseases associated with elevated or abnormal peripheral serotonin levels.
  • the treatment or prevention includes administering to a patient in need thereof a therapeutically effective amount of a TPHl inhibitor of the invention.
  • Biological assays can be used to determine the inhibitory effect of compounds against TPH (such as TPHl) in vitro and/or in vivo.
  • TPH such as TPHl
  • In vitro biochemical assays for human, mouse, and rat TPHl and human TPH2, PheOH, and TH may be used to measure inhibition of enzyme activity and the selectivity among TPHl, TPH2, PheOH, and TH.
  • the efficacy of these compounds can be determined, for example, by measuring their effect on intestinal 5-HT levels in rodents after oral administration.
  • a TPHl inhibitor of the invention include bone disease such as, for example, osteoporosis, osteoporosis pseudoglioma syndrome (OPPG), osteopenia, osteomalacia, renal osteodystrophy, Paget's disease, fractures, and bone metastasis,
  • the disease is osteoporosis, such as primary type 1 (e.g., postmenopausal osteoporosis), primary type 2 (e.g., senile osteoporosis), and secondary (e.g., steroid- or glucocorticoid-induced osteoporosis).
  • primary type 1 e.g., postmenopausal osteoporosis
  • primary type 2 e.g., senile osteoporosis
  • secondary e.g., steroid- or glucocorticoid-induced osteoporosis
  • the present invention further includes methods of treating or preventing bone fracture such as, for example, osteoporotic or traumatic fracture, or surgical fractures associated with an orthopedic procedure (e.g., limb lengthening, bunion removal, an increase in bone formation associated with a prosthesis, bone metastasis, or spinal fusion).
  • bone fracture such as, for example, osteoporotic or traumatic fracture, or surgical fractures associated with an orthopedic procedure (e.g., limb lengthening, bunion removal, an increase in bone formation associated with a prosthesis, bone metastasis, or spinal fusion).
  • cardiovascular diseases such as atherosclerosis and pulmonary hypertension (PH), including idiopathic or familial PH, and also including PH associated with or brought on by other diseases or conditions.
  • PH disease is pulmonary arterial hypertension (PAH).
  • PAH idiopathic
  • FPAH familial
  • APAH associated
  • PAH PAH which is associated with other medical conditions including, for example, (1) collagen vascular disease (or connective tissue disease) which include autoimmune diseases such as scleroderma or lupus; (2) congenital heart and lung disease; (3) portal hypertension (e.g., resulting from liver disease); (4) HIV infection; (5) drugs (e.g., appetite suppressants, cocaine, and amphetamines; (6) other conditions including thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia,
  • drugs e.g., appetite suppressants, cocaine, and amphetamines
  • other conditions including thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia,
  • APAH can also be PAH associated with abnormal narrowing in the pulmonary veins and/or capillaries such as in pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis.
  • PVOD pulmonary veno-occlusive disease
  • PPHN pulmonary capillary hemangiomatosis
  • Further diseases treatable or preventable by the methods of the invention include metabolic diseases such as diabetes and hyperlipidemia; pulmonary diseases such as chronic obstructive pulmonary disease (COPD), and pulmonary embolism; gastrointestinal diseases such as IBD, colitis, chemotherapy- induced emesis, diarrhea, carcinoid syndrome, celiac disease, Crohn's disease, abdominal pain, dyspepsia, constipation, lactose intolerance, MEN types I and II, Ogilvie's syndrome, pancreatic cholera syndrome, pancreatic insufficiency,
  • metabolic diseases such as diabetes and hyperlipidemia
  • pulmonary diseases such as chronic obstructive pulmonary disease (COPD), and pulmonary embolism
  • gastrointestinal diseases such as IBD, colitis, chemotherapy- induced emesis, diarrhea, carcinoid syndrome, celiac disease, Crohn's disease, abdominal pain, dyspepsia, constipation, lactose intolerance, MEN types I and II, Ogil
  • liver diseases such as chronic liver disease
  • cancers such as liver cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, and bone cancer
  • osteosarcoma chrondrosarcoma, Ewings sarcoma, osteoblastoma, osteoid osteoma, osteochondroma, enchond oma, chondromyxoid fibroma, aneurysmal bone cyst, unicameral bone cyst, giant cell tumor, and bone tumors
  • blood diseases e.g., myeoloproliferative syndrome, myelodysplasia syndrome, Hodgkin's lymphoma, non-Hodgkin's lymphoma, myeloma, and anemia such as aplastic
  • the compounds of the invention are also useful in the treatment and prevention of serotonin syndrome.
  • the present invention includes methods of lowering plasma cholesterol, lowering plasma triglycerides, lowering plasma glycerol, lowering plasma free fatty acids in a patient by administering to said patient a therapeutically effective amount of a compound of the invention.
  • the compounds of the invention are also useful in the treatment and prevention of inflammatory disease, such as allergic airway inflammation (e.g., asthma).
  • inflammatory disease such as allergic airway inflammation (e.g., asthma).
  • an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal.
  • an in vitro cell can be a cell in a cell culture.
  • an in vivo cell is a cell living in an organism such as a mammal.
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • "contacting" the enzyme with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having the TPH1 enzyme, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the TPH1 enzyme.
  • the term "individual” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the phrase "therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • treating refers to 1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), or 2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).
  • preventing refers to inhibiting onset or worsening of the disease; for example, in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
  • One or more additional pharmaceutical agents or treatment methods can be used in combination with the compounds of the present invention for treatment or prevention of various diseases, disorders or conditions disclosed herein.
  • the agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially in separate dosage forms.
  • Example pharmaceutical agents that may be useful in a combination therapy for blood disorders like blood cancers include parathyroid hormone, anti-sclerostin antibodies, kathepsin K inhibitors, and anti-Dickopff 1.
  • Example pharmaceutical agents that may be useful in a combination therapy for cancer include leuprolide, gosereiin, buserelin, flutamide, nilutamide, ketoconazole, aminoglutethimide, mitoxantrone, estramustine, doxorubicin, etoposide, vinblastine, paclitaxel, carboplatin, and vinorelbine.
  • Therapies that can be combined with TPH inhibition include radiation therapy, high- intensity focused ultrasound, or surgery (e.g., removal of diseased tissues).
  • drugs for use in treating cancer include testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, GnRH-analogues, temozolomide, bavituximab, cyclophosphamide, fluorouracil, fulvestrant, gefitinib, trastuzumab, IGF-1 antibodies, lapatinib, methotrexate, olaparib, BSI-201, pazopanib, rapamycin, ribavirin, sorafenib, sunitinib, tamoxifen, docetaxel, vataHnib, bevacizumab, and octreotide.
  • Example pharmaceutical agents that may be useful in combination therapy for cardiovascular or pulmonary diseases include endothelin receptor antagonists such as ambrisentan, BMS-193884, bosentan, darusentan, SB-234551, sitaxsentan, tezosentan and macitentan.
  • Anticoagulants such as warfarin, acenocoumarol, phenprocoumon, phenindione, heparin, fondaparinux, argatroban, bivaliiudin, lepirudin, and ximelagatran may also be useful in combination therapy.
  • Pharmaceutical agents for combination therapy further include calcium channel blockers like amlodipine, felodipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, lacidipine, lercanidipine, phenylalkylamines, verapamil, gallopamil, diltiazem, and menthol.
  • Prostacyclins like epoprostenol, iloprost and treprostinil may also be combined with the TPH inhibitors of the invention.
  • PDE5 inhibitors like sildenafil, tadalafil, and vardenafil
  • diuretics like furosemide, ethacrynic acid, torasemide, bumetanide,
  • hydrochlorothiazide spironolactone, mannitol, nitric oxide or nitric oxide releasers, and soluble guanylate cyclase stimulators, such as riociguat.
  • soluble guanylate cyclase stimulators such as riociguat.
  • further pharmaceutical agents for combination therapy include APJ receptor agonists (WO 2013/11 11 10); IP receptor agonists (WO 2013/105057; WO 2013/105066; WO 2013/105061; WO 2013/105063; WO 2013/105065; WO 2013/105058); and PDGF receptor inhibitors (WO 2013/030802).
  • Example pharmaceutical agents that may be useful in combination therapy for metabolic disorders include HSL inhibitors such as those disclosed in International Patent Publications WO2006/074957; WO2005/073199; WO2004/1 1 1031 ; WO2004/1 1 1004; WO2004/035550; WO2003/051841; WO2003/051842; and WO2001/066531.
  • Example pharmaceutical agents that may be useful in combination therapy for bone disorders and diseases include bisphosphantes such as etidronate, clodronate, tiludronate, pamidronate, neridronate, oipadronate, alendronate, ibandronate, risedronate, cimadronate, zoledronate, and the like.
  • Serotonin receptor modulators such as 5-HTIB , 5-HT 2 A, and 5-HT 2 B agonists or antagonists, may also be useful in combination therapy for bone disease.
  • SS I selective serotonin reuptake inhibitors
  • anti-serotonin antibodies include beta blockers such as IPS339, ICI1 18,551, butaxamine, metipranolol, nadol, oxprenolol, penbutolol, pindolol, propranolol, timolol, and sotalol
  • Further useful agents for combination therapy for the treatment of bone disorders, such as osteoporosis include teriparatide, strontium ranelate, raloxifene, and denosumab,
  • the compounds of the invention can be administered to patients (animals and humans) in need of such treatment in appropriate dosages that will provide prophylactic and/or therapeutic efficacy.
  • the dose required for use in the treatment or prevention of any particular disease or disorder will typically vary from patient to patient depending on, for example, particular compound or composition selected, the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors.
  • the appropriate dosage can be determined by the treating physician.
  • a compound of this invention can be administered orally, subcutaneously, topically, parenteral ly, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • compositions can be administered one to four or more times per day.
  • a treatment period can terminate when a desired result, for example a particular therapeutic effect, is achieved. Or a treatment period can be continued indefinitely.
  • the pharmaceutical compositions can be prepared as solid dosage forms for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules and the like).
  • a tablet can be prepared by compression or molding.
  • Compressed tablets can include one or more binders, lubricants, glidants, inert diluents, preservatives, disintegrants, or dispersing agents, Tablets and other solid dosage forms, such as capsules, pills and granules, can include coatings, such as enteric coatings,
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders.
  • Liquid dosage forms for oral administration can include, for example, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • Suspensions can include one or more suspending agents
  • Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • compositions and compounds of the present invention can be administered by aerosol which can be administered, for example, by a sonic nebulizer.
  • compositions of this invention suitable for parenteral administration include a compound of the invention together with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions.
  • the composition can be in the form of a sterile powder which can be reconstituted into a sterile injectable solutions or dispersion just prior to use.
  • Method A Waters BEH C18, 3,0 x 30 mm, 1.7 ⁇ , was used at a temperature of 50 °C and at a flow rate of 1.5 mL/min, 2 ⁇ injection, mobile phase: (A) water with 0.1% formic acid and 1% acetonitrile, mobile phase (B) MeOH with 0.1% formic acid; retention time given in minutes.
  • Method A details: (1) ran on a Binary Pump G1312B with UV/Vis diode array detector G1315C and Agilent 6130 mass spectrometer in positive and negative ion electrospray mode with UV PDA detection with a gradient of 15-95% (B) in a 2.2 min linear gradient (II) hold for 0.8 min at 95% (B) (III) decrease from 95-15% (B) in a 0.1 min linear gradient (IV) hold for 0.29 min at 15% (B);
  • Method B An Agilent Zorbax Bonus RP, 2.1 x 50 mm, 3.5 ⁇ , was used at a temperature of 50 °C and at a flow rate of 0.8 mL/min, 2 ⁇ , injection, mobile phase: (A) water with 0.1% formic acid and 1% acetonitrile, mobile phase (B) MeOH with 0.1% formic acid; retention time given in minutes, Method details: (I) ran on a Binary Pump G1312Bwith UV/Vis diode array detector G1315C and Agilent 6130 mass spectrometer in positive and negative ion electrospray mode with UV-detection at 220 and 254 nm with a gradient of 5-95% (B) in a 2.5 min linear gradient (II) hold for 0.5 min at 95% (B) (III) decrease from 95-5% (B) in a 0.1 min linear gradient (IV) hold for 0.29 min at 5% (B).
  • Method C An API 150EX mass spectrometer linked to a Shimadzu LC- 1 OAT LC system with a diode array detector was used.
  • the spectrometer had an electrospray source operating in positive and negative ion mode.
  • LC was carried out using an Agilent ZORBAX XDB 50 x 2.1 mm CI 8 column and a 0.5 mL/minute flow rate.
  • Solvent A 95% water, 5% acetonitrile containing 0.01% formic acid;
  • Solvent B acetonitrile. The gradient was shown as below.
  • Microwave experiments were carried out using a Biotage InitiatorTM, which uses a single- mode resonator and dynamic field tuning. Temperatures from 40-250 °C were achieved, and pressures of up to 20 bars were reached.
  • Preparative HPLC purification was carried out using either a CI 8 -reverse-phase column from Genesis (CI 8) or a C6-phenyl column from Phenomenex (C6 Ph) (100 x 22.5 mm i.d. with 7 micron particle size, UV detection at 230 or 254 nm, flow 5-15mL/min), eluting with gradients from 100-0 to 0-100 % water/acetonitrile or water/MeOH containing 0.1% formic acid. Fractions containing the required product (identified by LCMS analysis) were pooled, the organic fraction removed by evaporation, and the remaining aqueous fraction lyophilised, to give the product. Chiral HPLC was carried out using a Chiralpak AD column, 4.4 mm x 250 mm, particle size 5 micron
  • the chiral alcohols drawn below are shown in their absolute configuration (unless otherwise shown). Their enantiopurity (% ee) can be determined via Mosher ester analysis and analyzed as described in the literature (Dale, J, A, & Mosher, H. S. Nuclear Magnetic Resonance Enantiomer Regents, Configurational Correlations Via Nuclear Magnetic Resonance Chemical Shifts Of Diastereomeric Mandelate, O-Methylmandelate, and alpha-Methoxy alpha- Trifluoromethylphenylacetate (MTPA) Esters. J, Am. Chem. Soc. 95, 512-519 (1973)).
  • the chiral alcohols of the invention are preferably enantiomerically enriched, for example, to > 95% ee,
  • Step 1 Potassium /-butoxide (16.3 g, 145 mmol) was dissolved in DMSO (100 mL). To this solution was added 3-methyl pyrazole (10.4 g, 120 mmol) and the reaction was heated at 50 °C for 30 min. l ,4-Dibromo-2-fluorobenzene (31 g, 120 mmol) was then added and the reaction stirred at 50 °C for 16 h. The reaction was cooled to RT and extracted with water and EtOAc, washed with brine, dried over Na 2 S0 4 , and then filtered and concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtO Ac/heptane) provided 1 -(2,5- dibromophenyl)-3-methyl-lH-pyrazole.
  • Step 2 l -(2,5-dibromophenyl)-3-methyl-lH-pyrazole (23.0 g, 73 mmol) from Step 1 was dissolved in 200 mL of THF and cooled to 0 °C. /-Propyl magnesium chloride (2.0 M in THF, 40 mL) was added dropwise and the reaction was stirred for 45 min, then ethyl trifluoroacetate (10.5 mL) was added. The reaction was stirred for 30 min at 0 °C, then 10% HC1 is added dropwise (400 mL), The reaction was extracted with water and EtOAc, washed with brine, dried over Na 2 S0 4 , filtered, and then concentrated in vacuo.
  • Step 3 METHOD A: Pentamethylcyclopentadienyl iridium (III) chloride dimer (CAS# 12354- 84-6) (10,4 mg) and (lR,2R)-(-)-N-(4-toluene sulfonyl)-l ,2-diphenyl ethylene diamine (CAS# 144222-34-4) (9.2 mg) were combined in water ( 120 mL), then heated to 50 °C for 5 h to provide the "Iridium complex.” l-[4-Bromo-2-(3 -methyl- 1 H-pyiazol- 1 -yl)phenyl] -2,2,2- trifluoroethanone (16 g, 48 mmol) was dissolved in acetonitrile (120 mL) to which the Iridium complex and potassium formate (3.1 g, 3,7 mmol) were added.
  • reaction mixture was heated to 50 °C for 8 h, The reaction mixture was then cooled to RT, partitioned between water and EtOAc, and extracted. The combined organic layers were washed with brine, dried over Na 2 S0 4 , filtered, and concentrated in vacuo. Recrystallization from hot heptane (200 mL) provided the title compound.
  • METHOD B Alternatively, the trifiuoromethyl (or other prochiral) ketones of formula G or J (scheme 2) were asymmetrically reduced as follows (see for example: Corey, E. J. & Link, J. O, A General, Catalytic, and Enantioselective Synthesis of Alpha-amino Acids, J, Am. Chem. Soc. 114, 1906-1908 (1992)): Catechol borane (95 mL, 1 M in THF) and (S)-2-methyl-CBS oxazaborolidine (2.6 g, 9.6 mmol) were mixed in a jacketed glass reactor. The mixture was stirred at RT for 20 min, then the jacket was cooled to -78 °C.
  • reaction mixture was quenched with 1 N NaOH, extracted with ether, washed with brine, dried over Na 2 S04, and concentrated in vacuo. Purification on normal phase silica gel chromatography (EtO Ac/heptane) provided the product as a viscous oil.
  • Step 1 Diisopropylamine (4.40 mL, 31.4 mmol) was dissolved in THF (28 mL) and cooled to
  • Step 2 l -(5-bromo-2-fluoi phenyl)-2,2,2-trifluoroethanone (2.20 g, 8.12 mmol) from Step 1, K2CO3 (1.68 g, 12.2 mmol), and 3-methyl-lH-pyrazole (1.33 g, 1 .2 mmol) were stirred in toluene (10 mL). The reaction was then heated to 110 °C for 16 h. The reaction was cooled, and water and EtOAc were added. The toluene-EtOAc layer is removed in vacuo, and then the reaction is extracted with water and EtOAc, washed with brine, and dried over Na S04, filtered, and concentrated in vacuo.
  • Step 3 The title compound was prepared using the Iridium complex-catalyzed hydrogenation as described for Intermediate 1, (R)-l-(4-bromo-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethanol.
  • Step 1 Potassium /-butoxide (3.9 g, 0.33 mmol) was dissolved in DMSO (25 mL). To this solution was added 3 -methyl pyrazole (2.7 g, 0.33 mmol) and the reaction was heated at 50 °C for 30 min. l-Bromo-4-chloro-2-fluorobenzene (4.6 g, 0.22 mmol) was then added and the reaction was stirred at 50 °C for 16 h. The reaction was cooled to RT and extracted with water and EtOAc, washed with brine, and dried over Na 2 S0 4) filtered and concentrated in vacuo.
  • Step 2 The mixture from Step 1 (8 g, 0.39 mmol) was dissolved in 160 mL of THF and cooled to 0 °C. /-Propyl magnesium chloride (2.0 M in THF, 23 mL) was added dropwise and the reaction stirred for 45 min, then ethyl trifluoroacetate (6 mL) was added. The reaction was stirred for 30 min at 0 °C, then 10% HC1 was added dropwise (40 mL). The reaction was extracted with water and EtOAc, washed with brine, and dried over Na 2 S0 4 , filtered, and concentrated in vacuo.
  • Step 3 The title compound was prepared using the Iridium complex-catalyzed hydro genation, as described for intermediate 1 (R)-l-(4-bromo-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethanol.
  • reaction was heated in a sealed tube to 130 °C for 12 h and then cooled to RT, The solids were filtered and the product was purified by normal phase silica gel chromatography (EtOAc:petroieum ether) to to provide the title compound as a white solid.
  • Step 1 4-Bromo-2-methyl-lH-benzimidazole (500 mg, 2.37 mmol) was dissolved in THF (8 mL) and cooled to -78 °C. /?-Butyllithium (2,3 mL, 2.5 M in hexanes, 5.7 mmol) was added dropwise and the reaction was stirred at -78 °C for 30 min. Trifliioroacetic acid ethyl ester (339 //L, 2,8 mmol) was added and the reaction was stirred at 0 °C for 1 h.
  • Step 2 The title compound was prepared using the iridium complex-catalyzed hydrogenation, as described for Intermediate 1 (R)-l-(4-bromo-2-(3-methyl-lH-pyrazol-l-yl)phenyi)-2,2,2 ⁇ trifluoroethanol.
  • Step 1 l-(2-bromo-5-chloiOphenyl)-3-methyl-lH-pyrazole/l-(2-bi mo-5-chloiOphenyl)-5- methyl-lH-pyrazole mixture (Intermediate 3, step 1) (1.00 g, 3.68 mmol) was dissolved in THF (6 mL) and cooled to 0 °C. /-Propyl magnesium chloride (2.76 mL, 2.0 M in THF, 5.52 mmol) was added dropwise and allowed to warm to RT over 30 min. The reaction was then cooled to -15 °C. Acetyl chloride (481 //L, 5.5 mmol) was added and the reaction was warmed to RT for 3 h.
  • Step 2 l-[4-Chloro-2-(3-methyl-pyrazol-l-yl)-phenyl]-ethanone (400 mg, 1.70 mmol) from Step 1 was dissolved in MeOH (10 mL) and cooled to 0 °C. NaBH 4 (129 mg, 3.41 mmol) was added portionwise, then the reaction was warmed to RT, stirred for 30 min, then quenched with acetone. The MeOH was removed in vacuo then the residue was partitioned between water and EtOAc and extracted several times. The combined organic layers were washed with brine, dried over Na 2 S0 4 , filtered, and concentrated in vacuo. Purification by normal phase silica gel column chromatography (CH2Cl 2 /MeOH/NH 4 OH) provided the title compound.
  • Step 1 l-(2-biOmo-5-chlorophenyl)-3-methyl-lH-pyrazole/l-(2-bi mo-5-chlorophenyl)-5- methyl-lH-pyrazole mixture (Intermediate 3, step 1) (1 ,00 g, 3.68 mmol) was dissolved in THF (6 mL) then cooled to 0 °C, /-Propyl magnesium chloride (2,76 mL, 2.0 M in THF, 5.52 mmol) was added dropwise and the reaction was warmed to RT for 30 min. The reaction was then cooled to -15 °C and paraformaldehyde (166 mg, 5.5 mmol) was added.
  • Step 2 4-Chloi -2-(3-methyl-pyrazol-l-yl)-benzaldehyde (446 mg, 2,03 mmol) from Step 1 was dissolved in MeOH (14 mL) and cooled to 0 °C. NaB3 ⁇ 4 (175 mg, 4.61 mmol) ) was added portionwise. The reaction mixture was allowed to warm to RT, and after 90 min was quenched with acetone. The MeOH was removed in vacuo. The residue was partitioned between water and EtOAc and then extracted. The combined organic layers were washed with brine, dried over Na2S0 4 , filtered, and concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtO Ac/heptane) provided the title compound,
  • Step 1 To a solution of phenol (415 mg, 4.5 mmol) in 60 mL of DMF was added NaH (60%, 6.0 mmol) at 0 °C, The reaction was stirred for 1 h, then 2-fluoro-6-(piperidin-l-yi)benzonitrile (CAS# 646989-68-6) (612 mg, 3.0 mmol) was added and the reaction stirred for 48 h at RT. The reaction mixtme was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na 2 S0 4) then concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtO Ac/heptane) provided 2- phenoxy-6-(piperidin-l-yl)benzomtnle as an off-white solid.
  • Step 2 To 2-phenoxy-6-(piperidin-l-yl)benzonitrile (250 mg, 0.9 mmol) from Step 1 in 20 mL of MeOH was added Raney Nickel (5%) and NH 4 OH (2 mL). The reaction was stirred under 1 atm of 3 ⁇ 4 at RT for 2 h. The solid was filtered away and the filtrate was concentrated in vacuo to provide the title compound as a viscous oil.
  • Step 1 l-Bromo-4-chloro-2-(2-methoxy-ethoxy)-benzene (CAS# 1245563-20-5) (5.00 g, 18.8 mmol) was dissolved in THF (30 mL) and cooled to 0 °C. /-Propylmagnesium bromide (11.3 mL, 2.0 M in THF, 22.6 mmol) was added dropwise, and the reaction was stirred at 10 °C for 30 min, then warmed to RT for 16 h. The reaction was then cooled to -15 °C and trifluoroacetic acid ethyl ester (3.37 mL, 28.2 mmol) was added.
  • Step 2 The title compound was prepared using the Iridium complex-catalyzed hydrogeneation as described for Intermediate 1 (R)-l -(4-bromo-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethanol.
  • Step 1 To the solution of 2-chloro-6-methylnicotinic acid (5 g, 29.1 mmol) in CH 2 C1 2 (40 mL) was added oxalyl dichloride (8.1 g, 63.8 mmol) at 0 °C and the reaction mixture was stirred for 2 h. The mixture was concentrated and 40 mL of methanol was then added at 0 °C and the reaction mixture was stirred at RT for 12 h. The mixture was then concentrated in vacuo and extracted with EtOAc. The combined organic layers were washed with brine, dried ove a2S04, filtered, and concentrated in vacuo to provide methyl 2-chloro-6-methylnicotinate that is used without further purification as a light yellow solid.
  • Step 2 To a solution of 3 -methyl- lH-pyrazole (1.1 g, 13.4 mmol) in DMF (5 ml) was added sodium hydride (1.0 g, 60% in oil) at 0 °C. The reaction mixture was stirred for ⁇ h at 0 °C and then . A solution of methyl 2-chloro-6-methylnicotinate (4.3 g, 23.16 mmol) in DMF (5 mL) was added dropwise to the reaction mixture at 0 °C. After addition, the mixture was heated to 80 °C and stirred for 12 h. After this time, the mixture was poured into ice- ater and extracted and extracted with EtOAc.
  • Step 3 To a solution of methyl 6-methyl-2-(3-methyl-lH-pyrazol-l-yl)nicotinate (3.7 g, 16 mmol) and trimethyl(trifiuoromethyl)silane ( 1.4 g, 80.2 mmol) in toluene (60 ml), was added dropwise at -78°C and then the solution of tetrabutyl ammonium fluoride (1.6 mL,l .0 M in THF) was added dropwise to the reaction mixture at -78 °C. After addition, the mixture was warmed slowly up to RT and stirred for 12 h. The reaction mixture was concentrated and the resulting residue was dissolved in methanol (30 mL).
  • Step 4 A solution of (S)-(-)-2-Butyl-CBS-oxazaborolidine solution (3,0 ml 1.0 M in toluene) and catecholborane (30 ml 1.0 M in THF) was stirred at RT for 30 min. The mixture was then cooled to -70 °C and 2,2 J 2-trifluoiO-l-(6-methyl-2-(3-methyl-i r-I-pyrazol-l -yl)pyridin-3- yl)ethanone (1 g, 2.9 mmol) in THF (16 mL) was added dropwise. After addition, the reaction mixture was warmed up to -32 °C and stirred for 12 h.
  • Step 2 To a solution of 5-bi mo-[l, -biphenyl]-2-carboxylic acid (5 g, 18.2 mmol) in MeOH (30 mL) was added SOCl 2 (10 mL) dropwise. The reaction mixture was heated to 70 °C for 2 h, then cooled to RT.
  • Step 3 A solution of methyl 5-bromo-[l ,l'-biphenyl]-2-carboxylate (2,2 g, 6.9 mmol) in THF (50 mL) was cooled to 0 °C. LiAlI3 ⁇ 4 (380 mg, 10 mmol) was added slowly. The reaction mixture was stirred at RT for 2 h, after which water (1 mL) was added slowly to quench the reaction. The solid was removed by filtration and the filtrate was concentrated in vacuo to provide (5-bromo- [l,r-biphenyl3-2-yl)methanol as a white solid that was used directly without further purification.
  • Step 5 To a solution of 5-bromo-[l,r-biphenyl]-2-carbaldehyde (1.9 g, 7.3 mmol) and was added TMSCF3 (1.2g, 8.7 mmol) in THF (20 mL) and cooled to 0 °C. To this solution was added TBAF (1.46 mL, 1M in THF) and the reaction mixture was warmed to RT for 3 h. After this time, the mixture was treated with 3 N HC1 (5 mL) and stirred for 12 h. Then the reaction mixture was diluted with water and extracted with ethyl acetate.
  • Step 6 To a solution of l-(5-biOmo-[l,l'-biphenyl]-2-yl)-2,2,2-trifluoroethano (1.8 g, 5.5 mmol) in CH2CI2 (30 mL) was added Dess-Martin Periodinane (3g, 7.1 mmol). The reaction mixture was stirred at RT for 2 h and then the solids were filtered. The resultant filtrate was concentrated in vacuo.
  • Step 7 l-(5-Bromo-[l,l'-biphenyl]-2-yl)-2 J 2,2-trifluoiOethanone (1.3 g, 3.9 mmol) in CH3CN (10 mL) was reduced to the chiral alcohol using the chiral iridium catalyst (METHOD A) at RT. The reaction mixture was then charged with potassium formate (725 mg, 8.6 mmol) and the mixture was stirred at 40 °C for 12 h, Then the reaction was diluted with water and extracted with ethyl acetate.
  • CH3CN chiral iridium catalyst
  • the reaction was heated to 87 °C for 24 h, then cooled to T, The solids were filtered away, and the solvent was removed in vacuo, then extracted with EtOAc, water, brine and dried over Na 2 S0 4 , The solvent was removed in vacuo to provide an off-white solid which was used without further purification.
  • Step 1 (3S)-8-Tert-butyl 3-ethyl 2,8-diazaspiro[4.5]decane-3,8-dicarboxylate [Example 24 in US Pat. Pub. No. 2012/0101280] (50 g, 160 mmol) in CH 2 C1 2 (500 mL), and Et 3 N (51.7 g, 512 mmol) was cooled to 0 °C. Benzyl chloroformate (34.1 g, 205 mmol) was added dropwise and the mixture was stirred at 0 °C for 3 h.
  • Step 2 To a solution of (S)-2-benzyl 8-tert-butyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3,8- tiicarboxylate (79 g, 160 mmol, Step 1) in CH 2 C1 2 (400 mL) was added TFA (182 g, 1600 mmol) dropwise at RT. The reaction mixture was stirred for 3 h then concentrated in vacuo. The residue was quenched with saturated NaHC0 3 and solid NaHC0 3 was added until no further gas evolution was noted. The mixture was extracted with EtOAc and the combined organic layers were concentrated in vacuo.
  • Step I (S)-2-Benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (2.4 g, 6.9 mmol) in HCl/dioxane (50 mL, 3.3 N) was stirred for 2 h at RT. The solvent was then removed in vacuo to provide (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate hydrochloride which was used directly without further purification.
  • Step 2 To a solution of (S)-2-benzyl 3-ethyl 2,8-diazaspiiO[4.5]decane-2,3-dicarboxylate hydrochloride and BOC 2 O (1.5 g, 6.9 mmol) in EtOH (50 mL) was added Pd/C (10%, 2.4 g) and HOAc (cat.). The mixture was degassed and blanked under H 2 then stirred at 45 °C at 50 psi of 3 ⁇ 4 for 12 h. The solid was filtered away and the filtrate concentrated in vacuo to provide the title compound as a viscous solid,
  • Step 1 To a solution of (R)-l-(4-bromo-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2 J 2,2- trifluoroethanol (160 mg, 0.2 mmol, Intermediate 1) in dioxane (2 mL) was added 2-amino-4,6- dichloropyrimidine (100 mg, 0.16 mmol) and Cs 2 C0 (48 ,g, 0.16 mmol). The reaction was heated to 80 °C for 16 h, cooled to RT, and filtered. The solvent was removed in vacuo and the residue was dissolved in a mixture of CH2CI2 and heptane, concentrated to half the volume, filtered, and concentrated again in vacuo. Purification via normal phase silica gel
  • Step 2 To a solution of 4-[(lR)-l -[4-bromo-2-(3-methylpyrazol-l-yl)phenyl]-2,2,2-trifluoiO- ethoxy]-6-chloro-pyrimidin-2-amine (125 mg, 0,3 mmol, Step 1) in dioxane (3 mL) was added (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (95 mg, 0.3 mmol) and Na 2 C0 3 (182 mg, 0.35 mmol). The reaction was heated to 90 °C for 130 h, then cooled to RT, filtered, and concentrated in vacuo, Purification by normal phase silica gel column
  • Step 3 To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l-(4-bromo-2-(3-methyl-lH- pyrazol-l-yl)phenyl)-2,2,2-trifluoi ethoxy)pyrimidin-4-yl)--2,8-diazaspiiO[4,5]decane-2,3- dicarboxylate (300 mg, 0.4 mmol, Step 2) in ethanol (2 mL) and water (0.5 mL) was added phenylboronic acid (143 mg, 0.8 mmol), PdCl 2 (PPh 3 ) 2 (41 mg, 0.058 mmol), and Cs 2 C0 3 (390 mg, 1 ,2 mmol). The reaction was heated to 60 °C for 16 h, then cooled to RT, filtered through celite and concentrated in vacuo. Purification by normal phase silica gel column
  • Step 4 A solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2 ⁇ 2-trifluoro-l-(3-(3-methyl-lH- pyrazoI-l-yl)-[l,r-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2 ⁇ 8-diazaspii [4.5]decane-2,3- dicarboxylate (240 mg, 0,4 mmol, Step 3) in EtOAc (5 mL) was hyrogenated using an H-Cube apparatus and a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 niL/min at RT.
  • Step 5 To a solution of (S)-ethyl 8-(2-amino-6-((R)-2,2 ; 2-trifluoiO-l-(3-(3-methyl-lH-pyrazol- 1 -yl)-[l , -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate (50 mg, 0.08 mmol) from Step 4 in THF (2.0 mL) and water (0,2 mL), was added lithium hydroxide monohydrate (58 mg, 0.05 mmol).
  • Step J To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l -(4-bromo-2-(3-metliyl-lH- pyrazol-l -yl)phenyl)-2,2,2-trifiuoi ethoxy)pyrimidin-4-yl)-2 J 8-diazaspii [4.5]decane-2,3- dicarboxylate (Step 2, Example lu) (300 mg, 0.4 mmol, Step 2) in ethanol (2 mL) and water (0.5 mL) was added (3,4-dimethylphenyl)boronic acid (120 mg, 0.8 mmol), PdCl 2 (PPh3)2 (41 mg, 0.058 mmol), and Cs 2 C0 3 (390 mg, 1.2 mmol).
  • Step 2 A solution of (S)-2-benzyl 3-ethyl 8-(2-amino ⁇ 6-((R)-l-(3' 3 4'-dimethyl-3-(3-methyl-lH- pyrazol- 1 -yl)-[l , 1 '-biphenyl]-4-yl)-2 J 2 ⁇ 2-trifluoi ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-2,3-dicarboxylate (220 mg, 0.3 mmol) in EtOAc (5 mL) was
  • Step 3 To a solution of (S)-ethyl 8-(2-amino-6-((R)-l-(3',4'-dimethyl-3-(3-methyl-lH-pyrazol-l- yl)-[l,r-biphenyl]-4-yl)-2,2,2-trifiuoroethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3- carboxylate (50 mg, 0.08 mmol) from Step 2 in THF (2.0 mL) and water (0.2 mL), was added lithium hydroxide monohydrate (58 mg, 0.05 mmol).
  • Step 7 To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l-(4-bromo-2-(3-methyl-lH- pyrazol-l-yl)phenyl)-2,2,2-trifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-2,3- dicarboxylate (Step 2, Example lu) (300 mg, 0.4 mmol, Step 2) in ethanol (2 mL) and water (0.5 mL) was added (3-(hydiOxymethyl)-4-methylphenyl)boronic acid (CAS# 1451391-54-0; 120 mg, 0.7 mmol), PdCl 2 (PPh ) 2 (41 mg, 0.058 mmol), and Cs 2 C0 3 (390 mg, 1.2 mmol).
  • Step 2 A solution of (S)-2 ⁇ benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoi -l-(3'- (hydroxymethyl)-4 , -metliyl-3-(3-methyl-lH-pyrazol-l-yl)-[l,r-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (200 mg, 0.24 mmol,) in EtOAc (5 mL) was hydrogenated using an H-Cube apparatus and a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 mL/min at RT.
  • Step 3 To a solution of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'-(hydiOxymethyl)-4'- methyl-3-(3-methyl-lH-pyrazol-l-yl)-[l,r-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2 t 8- diazaspiro[4.5]decane-3-caiboxylate (50 mg, 0.08 mmol) from Step 2 in THF (2.0 mL) and water (0.2 mL), was added lithium hydroxide nionohydrate (58 mg, 0.05 mmol).
  • Example lcr (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4'-(hydroxymcthyl)-3 , -methyI-3-(3- inethyl-lH-pyi'azol-l-yl)-[l,l , -bipheiiyl]-4-yl)ethoxy)pynmidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carl)oxylic acid
  • Example lcp (Si-S-i -amino ⁇ -tiRi-l-iS' ⁇ '-dimethyl-S-iS-itrifluorometh li-lH- razol-l- yl)-[l,l'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimi(lin-4-yI)-2,8-diazaspiro[4.5Jdecane-3- carboxylic acid
  • Step l A solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoiO-l-(2-(3-metliyl- lH-pyrazol-l-yl)-4-(l,2,3,6-tetrahydiOpyiidin-4-yl)phenyl)ethoxy)pyi'imidin-4-yl)-2 J 8- diazaspiro[4.5]decane-2,3-dicarboxy]ate (Example If) (150 mg, 0.15 mmol) in MeOH (5 mL) was hydrogenated in an H-Cube apparatus using a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 mL/min at RT.
  • Step 2 Hydrolysis of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-l -(2-(3-methyl-lH- pyrazol-l-yl)-4-(l ,2 ) 3,6-tetrahydiOpyi'idin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-2,3-dicarboxylate using the LiOH general method provided the title compound as an off-white solid.
  • Example 3a (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(2-(3-mcthyl-lH-pyrazol-l-yl)-4-(l- (methyIsulfonyI)piperidin-4-yI)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]dccane-3- carboxylic acid
  • Step 1 To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2 ; 2,2-trifluoi -l-(2-(3-methyl- lH-pyrazol-l -yl)-4-(l ,2,3,6-tetrahydropyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-2,3-dicarboxylate (320 mg, 0.413 mmol) in CH2CI2 (5.0 mL) was added methanesulfonyl chloride (47 mg, 0.41 mmol) and triethylamine (94 mg, 0.83 mmol), and the reaction was stirred for 1.5 h at RT and then concentrated in vacuo.
  • Step 2 A solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2 ; 2,2-tnfluoiO-l-(2-(3-methyl-lH- pyrazol-l-yl)-4-(l-(methylsulfonyl)-l ,2,3,6-tetrahydi pyiidin-4-yl)phenyl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (290 mg, 0.340 mmol, Step 1) in MeOH (10 mL) was hydrogenated in an H-Cube apparatus using a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 mL/min at RT.
  • Step 3 Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoi -l -(2-(3-methyl-lH-pyrazol-l - yl)-4-(l-(methyIsulfonyl)piperidin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4,5]decane-3-carboxylate using the LiOH general method provided the title compound as an off-white solid.
  • Step 1 To a solution of (S)-8-(2-amino-6-((R)-l -(4-bromo-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2 ) 2-ti'ifluoiOethoxy)pyrimidin-4-yl)-2-((benzyloxy)caibonyl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid (product of Step 3, Example 10m) (135 mg, 0.18 mmol) in dioxane (2 mL) was added (3-methoxy-4-(methoxycarbonyl)phenyl)boronic acid (84 mg, 0,4 mmol) and CS2CO3 (48 mg, 0.16 mmol), The reaction was heated to 80 °C for 16 h, cooled to RT, and filtered, The solvent was removed in vacuo.
  • Step 2 N-CBZ Deprotection was accomplished via method B to yield (S)-8-(2-amino-6-((R)- 2,2,2-trifluoro- l-(3'-methoxy-4'-(methoxycarbonyl)-3-(3-methyl- 1 H-pyrazol-l -yi)-[l , 1 '- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as an off- white solid.
  • Example 5a (S)-8-(2-amino-6-((R)-l-(3'-(ethoxycarbonyl)-3-(3-methyl-lH-pyrazol-l-yl)- [l, -biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]dccane-3- carboxylic acid
  • Step 1 To a solution of 9-borabicyclo[3.3.1]nonane (2.0 mL, 0.5 M in THF, 1.0 mmol) was added methyl but-3-enoate (100 ⁇ ,, 1.0 mmol) and stirred at RT for 2 h to prepare the 9- BBN/butane solution.
  • Step 2 To a solution of (S)-8-(2-amino-6-(( )-l-(4-bromo-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2 ) 8-diazaspiro
  • Step 3 N-CBZ Deprotection was accomplished via method B to provide (S)-ethyl 8-(2-amino-6- ((R)-2,2,2-trifluoi - 1 -(4-(4-methoxy-4-oxobutyl)-2-(3-methyl- 1 H-pyrazol - 1 -yi)phenyl) ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as an off-white solid.
  • Step 4 Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoiO-l-(4-(4-methoxy-4-oxobutyl)- 2-(3-methyI-l H-pyrazol- l-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate was carried out using the LiOH general method providing the title compound as an off-white solid.
  • Step I To a solution of (S)-8-(2-amino-6-((R)- 1 -(4-bromo-2-(3-methyI- 1 H-pyrazol- 1 - yl)phenyi)-2,2,2-trifluoi ethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid (product of Step 3, Example 10m) (240 mg, 0,33 mmol) in ethanol (8 mL) was added (E)-ethyl 3-(4,4,5,5-tetramethyl-l ; 3 J 2-dioxaborolan-2-yl)acrylate (110 mg, 0.49 mmol), PdCl 2 (PPh 3 )2 (20 mg, 0.049 mmol) and KHC0 3 (170 mg, 0.05 mmol).
  • Step 2 To a solution of ((S)-8-(2-amino-6-((R)-l -(4-((E)-3-ethoxy-3-oxoprop-l -en-l-yl)-2-(3- methyl-lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoiOethoxy)pyrimidin-4-yl)-2-((((2E J 4Z)-2- vinylhexa-2,4-dien-l-yl)oxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (180 mg, 0.15 mmol) in MeOH (5 mL) was hydrogenated in an H-Cube apparatus using a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 mL/min at RT.
  • Step 1 To a solution of (1 ⁇ )-1-[4- ⁇ 1 ⁇ 1 ⁇ -2-(3- ⁇ 1 ⁇ * ⁇ 1-1 ⁇ 1) ⁇ 1 ⁇ 6 ⁇ 1]-2 ⁇ 2,2- ⁇ ' ⁇ - ethanol (40 g, 138 mmol) in dioxane (400 mL) was added 4,6-dichloiOpyrimidin-2-amine (113 g, 690 mmol) and Cs 2 C0 3 (132 g, 405 mmol). The mixture was heated for 24 h at 80 °C. The reaction was then cooled to RT and filtered. The solvent was removed in vacuo, then CH 2 Ch and heptane was added. The solvent volume was reduced until a solid precipitated out.
  • Step 2 To a solution of 4-chloro-6-[(lR) ⁇ l -[4-chloro-2-(3-methylpyrazol-l-yl)phenyl]-2,2,2- trifluoroethoxy]pyrimidin-2-amine (57.3 g, 137 mmol, Step 1 ) in dioxane (500 mL) was added (S)-2-benzyl 3-ethyl 2,8-diazaspii [4,5]decane-2 5 3-dicarboxylate (48 g, 124,9 mmol), and NaHCOs (31.5 g, 375 mmol).
  • Step 3 N-CBZ Deprotection was accomplished via method B to provide (S)-ethyl 8-(2-amino-6- ((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2 J 2-trifiuoroethoxy)pynmidin-4-yl)- 2 ; 8-diazaspiro[4.5]decane-3-carboxylate an off-white solid.
  • Step 4 Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-l -(4-chloro-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provided the title compound as an off-white solid.

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Abstract

The present invention is directed to spirocyclic compounds which are inhibitors of tryptophan hydroxylase (TPH), particularly isoform 1 (TPH1), that are useful in the treatment of diseases or disorders associated with peripheral serotonin including, for example, gastrointestinal, cardiovascular, pulmonary, inflammatory, metabolic, and low bone mass diseases, as well as serotonin syndrome, and cancer.

Description

SPIROCYCLIC COMPOUNDS AS TRYPTOPHAN HYDROXYLASE INHIBITORS
FIELD OF THE INVENTION
The present invention is directed to spirocyclic compounds which are inhibitors of tryptophan hydroxylase (TPH), particularly isoform 1 (TPHl), that are useful in the treatment of diseases or disorders associated with peripheral serotonin including, for example,
gastrointestinal, cardiovascular, pulmonary, inflammatory, metabolic, and low bone mass diseases, as well as serotonin syndrome, and cancer.
BACKGROUND OF THE INVENTION
Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that modulates central and peripheral functions by acting on neurons, smooth muscle, and other cell types. 5-HT is involved in the control and modulation of multiple physiological and psychological processes. In the central nervous system (CNS), 5-HT regulates mood, appetite, and other behavioral functions. In the GI system, 5-HT plays a general prokinetic role and is an important mediator of sensation (e.g., nausea and satiety) between the GI tract and the brain. Dysregulation of the peripheral 5-HT signaling system has been reported to be involved in the etiology of several conditions (see for example: Mawe, G. M. & Hoffman, J, . Serotonin Signalling In The Gut- functions, Dysfunctions And Therapeutic Targets. Nature Reviews. Gastroenterology &
Hepaiology 10, 473-486 (2013); Gershon, M. D. 5-hydroxytryptamine (serotonin) In The Gastrointestinal Tract. Current Opinion in Endocrinology, Diabetes, and Obesity 20, 14-21 (2013); Lesu tel, M.5 Soil, C, Graf, R. & Ciavien, P.-A. Role of Serotonin In The Hepato- gastrointestinal Tract: An Old Molecule For New Perspectives. Cellular And Molecular Life Sciences : CMLS 65, 940-52 (2008)). These include osteoporosis (e.g. Kode, A, et at FOXOl Orchestrates The Bone-suppressing Function Of Gut-derived Serotonin, The Journal of Clinical Investigation 122, 3490-503 (2012); Yadav, V, K. et al. Pharmacological Inhibition Of Gut- derived Serotonin Synthesis Is A Potential Bone Anabolic Treatment For Osteoporosis. Nature Medicine 16, 308-12 (2010); Yadav, V. K, et al Lrp5 Controls Bone Formation By Inhibiting Serotonin Synthesis In The Duodenum, Cell 135, 825-37 (2008)), cancer (e.g. Liang, C, et ai Serotonin Promotes The Proliferation Of Serum-deprived Hepatocellular Carcinoma Cells Via Upregulation Of FOX03a. Molecular Cancer 12, 14 (2013); Soil, C. et al. Serotonin Promotes Tumor Growth In Human Hepatocellular Cancer. Hepatology 51, 1244-1254 (2010); Pai, V. P et al. Altered Serotonin Physiology In Human Breast Cancers Favors Paradoxical Growth And Cell Survival. Breast Cancer Research : BCR 11, R81 (2009); Engelman, K., Lovenberg, W. & Sjoerdsma, A. Inhibition Of Serotonin Synthesis By Para-chlorophenylalanine In Patients With The Carcinoid Syndrome. The New England Journal of Medicine 277, 1103-8 (1967)), cardiovascular (e.g. Robiolio, P. A, et ai Carcinoid Heart Disease : Correlation of High
Serotonin Levels With Valvular Abnormalities Detected by Cardiac Catheterization and
Echocardiography. Circulation 92, 790-795 (1995).), diabetes (e.g. Sumara, G,, Sumara, O., Kim, J. K. & Karsenty, G. Gut-derived Serotonin Is A Multifunctional Determinant To Fasting Adaptation. Cell Metabolism 16, 588-600 (2012)), atherosclerosis (e.g. Ban, Y. et al. Impact Of Increased Plasma Serotonin Levels And Carotid Atherosclerosis On Vascular Dementia.
Atherosclerosis 195, 153-9 (2007)), as well as gastrointestinal (e.g. Manocha, M. & Khan, W. I. Serotonin and GI Disorders: An Update on Clinical and Experimental Studies. Clinical and Translational Gastroenterology 3, el 3 (2012); Ghia, J.-E. et ai Serotonin Has A Key Role In Pathogenesis Of Experimental Colitis. Gastroenterology 137, 1649-60 (2009); Sikander, A,, Rana, S. V. & Prasad, K, K. Role Of Serotonin In Gastrointestinal Motility And Irritable Bowel Syndrome. Clinica Chimica Acta; International Journal of Clinical Chemistry 403, 47-55
(2009); Spiller, R, Recent Advances In Understanding The Role Of Serotonin In Gastrointestinal Motility In Functional Bowel Disorders: Alterations In 5-HT Signalling And Metabolism In Human Disease. Neitrogastroenterology and Motility: The Official Journal of The European Gastrointestinal Motility Society 19 Suppl 2, 25-31 (2007); Costedio, M. M., Hyman, N. & Mawe, G, M, Serotonin And Its Role In Colonic Function And In Gastrointestinal Disorders.
Diseases of the Colon and Rectum 50, 376-88 (2007); Gershon, M. D. & Tack, J. The Serotonin Signaling System: From Basic Understanding To Drug Development For Functional GI
Disorders. Gastroenterology 132, 397- 14 (2007); Mawe, G. M., Coates, M. D. & Moses, P. L. Review Article: Intestinal Serotonin Signalling In Irritable Bowel Syndrome. Alimentary Pharmacology & Therapeutics 23, 1067-76 (2006); Crowell, M. D. Role Of Serotonin In The Pathophysiology Of The Irritable Bowel Syndrome. British Journal of Pharmacology 141, 1285-93 (2004)), pulmonary (e.g. Lau, W. K. W. et al The Role Of Circulating Serotonin in The Development Of Chronic Obstructive Pulmonary Disease. PloS One 7, ©31617 (2012); Egermayer, P., Town, G. I. & Peacock, A. J. Role Of Serotonin In The Pathogenesis Of Acute And Chronic Pulmonary Hypertension. Thorax 54, 161-168 (1999)), inflammatory (e.g.
Margolis, K. G. et al Pharmacological Reduction of Mucosal but Not Neuronal Serotonin Opposes Inflammation In Mouse Intestine. Gut doi: 10.1 136/gutjnl-2013-304901 (2013);
Duerschmied, D. et al Platelet Serotonin Promotes The Recruitment Of Neutrophils To Sites Of Acute Inflammation In Mice. Blood 121, 1008-15 (2013); Li, N. et al Serotonin Activates Dendritic Cell Function In The Context Of Gut Inflammation. The American Journal of
Pathology 178, 662-71 (2011)), or liver diseases or disorders (e.g. Ebrahimkhani, M. R. et al Stimulating Healthy Tissue Regeneration By Targeting The 5-HT2B Receptor In Chronic Liver Disease. Nature Medicine 17, 1668-73 (2011)). The large number of pharmaceutical agents that block or stimulate the various 5-HT receptors is also indicative of the wide range of medical disorders that have been associated with 5-HT dysregulation (see for example: Wacker, D. et al Structural Features For Functional Selectivity At Serotonin Receptors, Science (New York N Y.) 340, 615-9 (2013)).
The rate-limiting step in 5-HT biosynthesis is the hydroxylation of tryptophan by dioxygen, which is catalyzed by tryptophan hydroxylase (TPH; EC 1.14.16.4) in the presence of the cofactor (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4). The resulting oxidized product, 5 -hydroxy tryptophan (5-HTT) is subsequently decarboxylated by an aromatic amino acid decarboxylase (AAAD; EC 4.1.1.28) to produce 5-HT. Together with phenylalanine hydroxylase (PheOH) and tyrosine hydroxylase (TH), TPH belongs to the pterin-dependent aromatic amino acid hydroxylase family.
Two vertebrate isoforms of TPH, namely TPH1 and TPH2, have been identified. TPH1 is primarily expressed in the pineal gland and non-neuronal tissues, such as entei chromaffin (EC) cells located in the gastrointestinal (GI) tract. TPH2 (the dominant form in the brain) is expressed exclusively in neuronal cells, such as dorsal raphe or myenteric plexus cells. The peripheral and central systems involved in 5-HT biosynthesis are isolated, with 5-HT being unable to cross the blood-brain barrier. Therefore, the pharmacological effects of 5-HT can be modulated by agents affecting TPH in the periphery, mainly TPH1 in the gut. A small number of phenylalanine-derived TPHl inhibitors are known. One example, p- chlorophenylalanine (pCPA), a very weak and unselective irreversible inhibitor of TPH, has proven effective in treating chemotherapy-induced emesis, as well as diarrhea, in carcinoid tumor patients, However, pCPA is distibuted centrally and, as a result, its administration has been linked to the onset of depression and other alterations of CNS functions in patients and animals. p-Ethynyl phenylalanine is a more selective and more potent TPH inhibitor than pCPA (Stokes, A, H. el al. p-Ethynylphenylalanine: A Potent Inhibitor Of Tryptophan Hydroxylase. Journal ofNeurochemisiry 74, 2067-73 (2000), but also affects central 5-HT production and, like pCPA, is believed to irreversibly interfere with the synthesis of TPH (and possibly other proteins).
More recently, bulkier phenylalanine-derived TPH inhibitors have been reported to reduce intestinal 5-HT concentration without affecting brain 5-HT levels (Zhong, H. et al Molecular dynamics simulation of tryptophan hydroxylase- 1 : binding modes and free energy analysis to phenylalanine derivative inhibitors. International Journal of Molecular Sciences 14, 9947-62 (2013); Ouyang, L. et al Combined Structure-Based Pharmacophore and 3D-QSA Studies on Phenylalanine Series Compounds as TPHl Inhibitors. International Journal of Molecular Sciences 13, 5348-63 (2012); Camilleri, M. LX-1031, A Tryptophan 5-hydroxylase Inhibitor, And Its Potential In Chronic Diarrhea Associated With Increased Serotonin.
Neurogastroenterology and Motility: The Official Journal of The European Gastrointestinal Motility Society 23, 193-200 (2011); Cianchetta, G, et al Mechanism of Inhibition of Novel Tryptophan Hydroxylase Inhibitors Revealed by Co-crystal Structures and Kinetic Analysis. Current chemical genomics 4, 19-26 (2010); Jin, H. et al. Substituted 3-(4-(l,3,5-triazin-2-yl)- phenyl)-2-aminopropanoic Acids As Novel Tryptophan Hydroxylase Inhibitors. Bioorganic & Medicinal Chemistry letters 19, 5229-32 (2009); Shi, Z.-C. et al Modulation Of Peripheral Serotonin Levels By Novel Tryptophan Hydroxylase Inhibitors For The Potential Treatment Of Functional Gastrointestinal Disorders. Journal of medicinal chemistry 51, 3684-7 (2008); Liu, Q. et al. Discovery And Characterization of Novel Tryptophan Hydroxylase Inhibitors That Selectively Inhibit Serotonin Synthesis In The Gastrointestinal Tract. The Journal of
Pharmacology and Experimental Therapeutics 325, 47-55 (2008)). There is a current need to selectively reduce intestinal 5-HT levels as a means for treating and preventing 5-HT-associated diseases. The TPH1 inhibitors described herein are intended to address this need. SUMMARY OF THE INVENTION
The present invention relates to a TPH-inhibiting compound of Formula I:
Figure imgf000006_0001
I
or a pharmaceutically acceptable salt thereof, wherein constituent variables are defined herein.
The present invention further relates to a pharmaceutical composition comprising a TPH- inhibiting compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
The present invention further relates to a method of inhibiting TPH, such as TPH1, by contacting the TPH enzyme with a compound of Formula I, or a pharmaceutically acceptable salt thereof.
The present invention further relates to a method of lowering peripheral serotonin in a patient comprising administering to the patient an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
The present invention further relates to a method of treating or preventing a disease in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
The present invention further relates to a compound of Formula Ϊ, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of disease in a patient. The present invention further relates to use of a compound of Formula I or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of disease in a patient. DETAILED DESCRIPTION
Compounds
The present invention relates to a TPH-inhibiting compound of Formula I:
Figure imgf000007_0001
I
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is Qj-io cycloalkyl, Ce-ioaryl, 4 to 10-membered heterocycloalkyl, or 5 to 10- membered heteroaryl;
L is O or NR4;
W is N or CR5;
X is N or CR6;
Y is N or CR7;
wherein only one of X and Y is N;
R1 is H, C[-to alkyl, Qj-iocycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, -(CRsR9),,OC(0)R10, -(CR8R9)p RnR12 , or -(CR8R9)PC(0)NR1 lRn, wherein said Ci-io alkyl, C3.10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and phenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from F, CI, Br, CN, Cm alkyl, and Ci-4 haloalkyl;
R2 and R3 are each independently selected from H, CM alkyl, and Ci^ haloalkyl;
R4 is H o Ci-4 alkyl; R5 and R6 are each independently selected from H, halo, and C alkyl;
R7 is H, C alkyl, C2-6 alkenyl, C3-io cycloalkyl, Cs-io cycloalkyl-CM alkyl, Ce-io aryl, C6- io aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, 5-10 membered heteroaryl, (5-10 membered heteroaryl)-CM alkyl, NR13R14, OR15, C(0)R)6 3 S(0)qR17, wherein said C alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C alkyl, C6-io aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)- C1-4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)- C 1-4 alkyl are each optionally substituted by 1, 2, or 3 substituents selected from halo, C1 -4 alkyl, C2-6 alkenyl, amino, Ci. alkyiamino, C2-8 dialkylamino, hydroxy, and C^ alkoxy;
R8 and R9 are each independently selected from H and Ci-4 alkyl;
Ri0 is Cs-6 alkyl optionally substituted by 1, 2 or 3 substituents independently selected from Ct-6 haloalkyl, C3-jo cycloalkyl, ORa, and NRcRd;
R11 and R12 are each independently selected from H and Ci-6 alkyl;
R13 is H or Ci-4 alkyl;
R14 is H, Ci- alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-Q-4 alkyl, C&-io aryl, Ce-io aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C!-4 alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl)-Ci-4 alkyl, C(0)RbI, C(0)ORal,
C(0)NRclRd!, S(0)Rbl, S(0)2Rbi, or S(0)2NRclRdl, wherein said CM alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C 1-4 alkyl, Ce-ioa yl, Ce-jo a yl-CM alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloaIkyl)-Ci-4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-Ct-4 alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CM alkyl, CM haloalkyl, CN, N02( ORal, SRal, C(0)Rbl, C(O)NR0lRdl ; C(0)ORal, 0C(O)Rbl, OC(0)NRc,Rdl, NRclRdl, NRc,C(0)Rbl, NRclC(0)ORal,
NRclC(0)NRolRdl, NRe,S(0)Rbl, NRclS(0)2Rbl, NRclS(0)2NRclRdi, S(0)RbJ, S(0)NRclRdl, S(0)2Rbl, and S(0)2NRclRdl ;
or R13 and R14 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7- membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents
independently selected from Ci-e alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, 5-6 membered heteroaryl, halo, CN, ORal, SRal, C(0)Rbl, C(0)NRCIRd!, C(0)ORat, OC(0)Rbl, OC(0)NReIRdl, NRclRdl, NRCIC(0)Rbl, NR0,C(O)NRclRd!, NRclC(0)ORat, S(0)RbI, S(0)NRclRdl, S(0)2Rbl, NRc,S(0)2Rbl J NRCIS(0)2NRclRdl, and S(0)2NRclRdI, wherein said Ci-6 alkyl, C3.7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-ioaryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORal, SRal, C(0)Rbl, C(0)NRCIRdl, C(0)ORa), OC(0)Rb!,
OC(0)NRc!Rd!, NRclRdi, NR0lC(O)Rbl, NRctC(0)NRclRdl, NR0lC(O)ORal, S(0)Rbl,
S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbl, NRclS(0)2NRclRdI, and S(0)2NRclRdl;
R15 is H, C alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl -C] -4 alkyl, Ce-jo aryl, Ce-io aryl-Cm alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalky^-C alkyl, 5-10 membered heteroaryl, or (5-10 membered hetei'oaryl)-Ci-4 alkyl, wherein said C alkyl, C3-7 cycloalkyl, C3-7 cycloa!kyl-C[.<i alkyl, Ce-io aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered
heterocycloalkyl, (4-10 membered heteiOcycloalkyl)-d -4 alkyl, 5-10 membered heteroaryl, and (5- 10 membered heteroaryl)-C alkyl are each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io ryl, 5-6 membered heteroaryl, CN, ORal, SRa!, C(0)RbI, C(0)NRc!Rdl, C(0)ORal, OC(0)RbI,
OC(0)NRclRdi ) NRclRdl, NRciC(0)Rb, } NRclC(0)NRclRdl, NRciC(0)ORaI, S(0)Rbl,
S(0)NRclRdi, S(0)2Rbl ; NRclS(0)2R l, NRclS(0)2NRclRdl > and S(0)2NRclRdl;
R16 is C1.4 alkyl or NR,8 R18b wherein said Ci-4 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-!o aryl, 5-6 membered heteroaryl, CN, ORal, SRal, C(0)Rbl, C(0)NRcIRdi, C(0)ORal, OC(0)RbI, OC(0)NRc!RdI, NRciRdl, NRclC(0)Rbl, NR0lC(O)NRclRdI, NRclC(0)ORaI, S(0)Rbl, S(0)NRclRdl, S(0)2Rbt, NRc,S(0)2Rbl 3 NR0lS(O)2NR lRd!, and S(0)2NRclRdl;
R17 is Ci-4 alkyl, NR! 8aRISb, or OR18c, wherein said C M alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6.io aryl, 5-6 membered heteroaryl, CN, ORnt, SRal, C(0)Rbl, C(0)NRciR<n, C(0)OR l, OC(0)Rbl, OC(0)NRclRdl, NRclRd', NRclC(0)Rb), NRclC(0)NRc,Rdl,
NRclC(0)ORal, S(0)Rbi, S(0)NRc,Rd!, S(0)2Rbl, NRclS(0)2Rbl, NRc,S(0)2NRclRdl } and S(0)2NRCIRdl;
R18a and R18b are each independently selected from H and C alkyl wherein said CM alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-ioaryl, 5-6 membered heteroaryl, CN, ORal, SRa!, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl, OC(O)NR0lRdl, NRclRdl, NRclC(0)Rbl, NRciC(0)NRciRdi, NR^QC OR31, S(0)Rbl } S(0)NRclRdI, S(0)2Rb!, NRelS(0)2Rbi,
NRCIS(0)2NRc!Rdi, and S(0)2NRclRdl;
or RI8ft and Rl8b together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1 , 2, or 3 substituents
independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, 5-6 membered heteroaryl, halo, CN, OR", SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl, OC(0)NRc,Rdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)ORal,
S(0)Rb!, S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbl, NRclS(0)2NRCIRdl, and S(0)2NRclRd!, wherein said C alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORal, SRaI, C(0)Rbl, C(0)NRdRdl, C(0)ORal, OC(0)Rb\
OC(0)NRclRdl, NRclRdl, NRclC(0)Rbf , NRclC(0)NRclR l } NRclC(0)ORal, S(0)Rbl,
S(0)NRclRdl, S(0)2Rb!, NRc,S(0)2Rbl, NRclS(0)2NRclRdl, and S(0)2NRclRdl;
R18c is H, Ci-6 alkyl, C3-10 cycloalkyl, Q^ cycioalkyl-Cm alkyl, Ce-io aryl, C6-io ryl-CM alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl)-Ci-4 alkyl, wherein said CM alkyl, C3-7 cycloalkyl, C3-io cycloalkyl-Ci-4 alkyl, Ce-io aryl, Ce-io aryl-Ct^ alkyl, 4-10 membered
heterocycloalkyl, (4-10 memberedheterocycloalkyl)-Ci.4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)~C 1 -4 alkyl are each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, CM alkyl, CM haloalkyl, CN, N02, ORal, SRaI, C(0)Rbl, C(0)NRclRdl, C(0)ORai ; OC(0)Rbl, OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRdC(0)ORaI, NR0lC(O)NRclRdl, NRclS(0)Rbt, NRclS(0)2R I, NRclS(0)2NRcIRdl, S(0)R l, S(0)NRclRdl, S(0)2Rbl, and S(0)2NRclRdl;
RA is H} Cy1, halo, C alkyl, C2-6 alkenyl, CN, N02, OR82, SRa2, C(0)Rb2, C(0)NRc2Rd2, C(0)ORa2, OC(0)Rb2, OC(0)NRc Rd2, NRc2Rd2, NRc C(0)Rb2, NRc C(0)ORa2,
NRc2C(0)NRc2Rd2, NRc2S(0)Rb2, NRc2S(0)2Rb2, NRc2S(0)2NRc2Rd2, S(0)R 2, S(0)NRc2Rd2, S(0)2Rb2, or S(0)2NRc2Rd2, wherein said C alkyl and C2.6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy1, halo, CM alkyl, C2- 6 alkenyl, C haloalkyl, CN, N02, ORa2, SR*2, C(0)Rb2, C(0)NRc2Rd2, C(0)ORa2, OC(0)Rb2, OC(0)NRc2Rd2 ; NRc Rd2, NRc2C(0)Rb2, NRc2C(0)ORa2, NRc C(0)NRc2Rd2, NRc2S(0)Rb2, NRc2S(0)2Rb2, NRc2S(0)2NRc2Rd2, S(0)Rb2, S(0)NRc2Rd2, S(0)2Rb2, and S(0)2NRc2Rd2; RB is H, Cy2, halo, Ci.fi alkyl, C2.6 alkenyi, Ci-6 haloalkyl, CN, N02j ORa3, SR33, C(0)Rb3, C(0)NRc3Rd3, C(0)ORa3 5 OC(0)Rb3, OC(0)NRc3Rd3 3 NRc3Rd3, NRc3C(0)Rb3, NRc3C(0)ORa3, NRc3C(0)NRc3Rd3, NRc3S(0)Rb3, NRc3S(0)2Rb3, NRc3S(0)2NRc3Rd3, S(0)Rb3, S(0)NRc3Rd3, S(0)2Rb3, or S(0)2NRc3Rd3, wherein said Ci-6 alkyl and C2.6 alkenyi are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from Cy2, halo, Ci-6 alkyl, C2- 6 alkenyi, C).6 haloalkyl, CN, N02, OR33, SR33, C(0)Rb3, C(0)NRc3Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc3Rd3, NRc3Rd3, NRc3C(0)Rb3, NRc3C(0)ORa3, NRc3C(0)NRc3Rd3, NRc3S(0)Rb3, NRclS(0)2Rb3, NRc3S(0)2NRc3Rd3, S(0)Rb3, S(0)NRc3Rd3, S(0)2Rb3, and S(0)2NRc3Rd3;
Rc and RD are each independently selected from H, halo, Ci-6 alkyl, C2-6 alkenyi, Ci-6 haloalkyl, CN, N02, ORa4, SRa4, C(0)Rb4, C(0)NRc4Rd4, C(0)ORa4, OC(0)R 4, OCCC R^R"4, NRc4Rd4, NRc4C(0)Rb4, NRc4C(0)ORa4 > NRc4C(0)NRc Rd4 ) NRc4S(0)Rb4, NRc S(0)2RM ( NRc4S(0)2NRc4Rd4 J S(0)Rb4, S(0)NRc4Rd4, S(0)2RM, and S(0)2NRe4Rd4; wherein said Ci.6 alkyl and C2-6 alkenyi are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from Ce-io ai'yl, C3-io cycloalkyl, 5-10 membered heteroaryl, 4- 10 membered
heterocycloalkyl, halo, Ci-6 alkyl, C2-6 alkenyi, Ci-6 haloalkyl, CN, NC ORa4, SRa4, C(0)Rb4, C(0)NRc4Rd4, C(0)ORa4, OC(0)Rb4, OC(0)NRc4Rd4, NRc4Rd\ NRo4C(0)Rb4, NRe4C(0)ORa4 ) NR^CCOJNR^R*14, NRc4S(0)Rb4, NRc4S(0)2R 4 } NRc4S(0)2NRc Rd4, S(0)Rb4, S(0)NRc Rd4, S(0)2Rb4, and S(0)2NRc Rd4;
Cy1 and Cy2 are each independently selected from Ce-io aryl, C3-io cycloalkyl, 5-10 membered heteroaryl, and 4- 10 membered heterocycloalkyl, each of which is optionally substituted by 1 , 2, 3, 4, or 5 substituents independently selected from RCy;
each RCy is independently selected from halo, Ci-6 alkyl, Ci-β haloalkyl, C2-6 alkenyi, C6-io aryl, C3-io cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, N02} ORaS, SRa5, C(0)Rb5, C(0)NRc5R 5, C(0)ORa5, OC(0)Rb5, OC(0)NRc5Rd5, NRc5Rds,
NRc5C(0)RbS, NRc5C(0)ORa5, NRc5C(0)NRc5Rd5, NRc5S(0)Rb5, NRc5S(0)2Rb5,
NRc5S(0)2NRcSRd5, S(0)RbS, S(0)NRc5Rd5, S(0)2Rb5, and S(0)2NRc5Rd5, wherein said Ci-6 alkyl, C2-0 alkenyi C6-io aryl, C3-10 cycloalkyi, 5-10 membered heteroaryl, and 4- 10 membered heterocycloalkyl are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from halo, Ci-β alkyl, CN, N02, ORaS, SRaS, C(0)Rb5, C(0)NRc5Rd5, C(0)ORaS, OC(0)Rb5, OC(0)NRc5Rd5, NRe5Rd5, NRc5C(0)Rb5, NRc5C(0)ORa5, NRc5C(O)NR0SRdS, NRc5S(0)Rb5, NRc5S(0)2RB5, NRe5S(0)2NRc5Rd5 } S(0)Rb5, S(0)NRc5Rd5, S(0)2Rb5, and
S(0)2NRc5Rd5;
each Ra, Ral, Ra2, R83, Ra4, and Ra5 is independently selected from H, C|.6 aikyl, C
haloalkyl, C2-6 alkenyl, Ce-io aryl, C3-io cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-io aryl-Ci-4 alkyl, C3-10 cycloalkyl-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- alky], or (4-10 membered heterocycloalkyl)-Ci-4 alkyl, wherein said Ci-β alkyl, C2-6 alkenyl, Ce- lo aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-to ryl- C alkyl, C3-io cycloa!kyl-Ci-4 alkyl, (5-10 membered heteroaryl)-C[.4 alkyl, and (4-10 membered heterocycloalkyl)- C 1.4 alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from CM alkyl, halo, CN, ORa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRe6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6,
NRc6C(0)ORa6, S(0)Rb5, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2RB6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
each Rbl, Rb2, Rb3, R 4 5 and Rb5 is independently selected from H, Ci-6 alkyl, CM
haloalkyl, C2-6 alkenyl, Ce-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4- 10 membered heterocycloalkyl, Ce-io iyl-Ci- alkyl, C3-]o cycloalkyl-C alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, or (4-10 membered heterocycloalkyl)-Ci-4 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, Cg. 10 aryl, C3-j a cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-io ryl- Ci-4 alkyl, C3-io cycloalkyl-C[.4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, and (4-10 membered heterocycloalkyl)-Ci.4 alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from CM alkyl, halo, CN, ORa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRe6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6R 6,
NRc6C(0)OR"6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
each R° , Rd, Rcl , Rdl , Rc2, Rd2, Rc3, Rd3, Rc4, Rd4, RcS, and Rd5 is independently selected from H, Ci-6 alkyl, CM haloalkyl, C2-6 alkenyl, C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-io ryl-CM alkyl, C3-io cycloalkyl-Ci-4 alkyl, (5- 10 membered heteroaryl)-Ci-4 alkyl, or (4-10 membered heteiOcycloalkyl)-Ci-4 alkyl, wherein said Ci-6 alkyl, C2-0 alkenyl, Ce-io a yl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl-Ci-4 aikyl, C3-io cycloalkyl-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, and (4-10 membered heterocycloalkyl)-Ci.4 alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C alkyl, halo, CN, OR'16, SRa6, C(0)Rb6 5 C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6,
NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2R 6,
NRc6S(0)2R fi, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6-, or
7 -membered heterocyclo alkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-e alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Cc-io aryl, 5-6 membered heteroaryl, halo, CN, ORa6, SRa6 } C(0)Rb6, C(0)NRe6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2R 6 ; NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said Ci-6 alkyl, C3. cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORn6, OC(0)Rb6 } OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rcl and Rd! together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3.7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, 5-6 membered heteroaryl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6 } NRe6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6 ;
S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRe6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said Ci-6 alkyl, C3 -7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, 0C(O)Rb6,
OC(0)NRe6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6,
S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rc2 and Rd2 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, and 5-6 membered heteroaryl, d .6 haloalkyl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6 5 S(0)Rb6, S(0)NRc6Rd6, S(0)2R 6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said Ci-6 alkyl, C3 -7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa5, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6 }
OC(0)Rb6, OC(0)NRe6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6R16, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rc3 and Rd3 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, 5-6 membered heteroaryl, Ci-6 haloalkyl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rh6, OC(0)NRe6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd£>,
NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6R 6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0) NRc5Rd6, wherein said Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SR 6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6,
OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6 } NRc6C(0)Rb6 ; NRc6C(0)NRc6Rd6, NRc6C(0)ORa6 ;
S(0)R 6, S(0)NR 6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rc4 and Rd4 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-to aryl, 5-6 membered heteroaryl, Ci-β haloalkyl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6,
NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NR 6Rd6, and S(0)2NRc6Rd6, wherein said Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRe6Rd6, NRc6C(0)Rb6 } NRc6C(0)NRc6Rd6, NRc6C(0)ORa6 J S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRe6S(0)2R 6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any R°5 and Rd5 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1 , 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, 5-6 membered lieteroaryl, Ci-e haloalkyl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)R 6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRe6Rd6,
NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6 ; NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said C[-6 alkyl, C3.7 cycloalkyl, 4-7 membered heterocycloalkyi, Ce-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6,
OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRC6C(0)Rb6, NRe6C(0)NRc5Rd6, NRc6C(0)ORa6, S(0)Rb6 s S(0)NRc6Rd6, S(0)2Rb6, NR 6S(0)2Rb6 } NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
each Ra6, Rb6, Rc6, and Rd6 is independently selected from H, C]-4 alkyl, C2-4 alkenyl, C3.7 cycloalkyl, phenyl, 5-6 membered lieteroaryl, and 4-7 membered heterocycloalkyi, wherein said C[-4 alkyl, C2.4 alkenyl, C3-7 cycloalkyl, phenyl, 5-6 membered lieteroaryl, and 4-7 membered heterocycloalkyi are each optionally substituted by 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C alkyl, C alkoxy, Ci^ a!kylthio, CM alkylamino, and di(Ci-4 alkyl)amino;
n is 1 or 2;
p is 1 , 2, or 3; and
q is 1 or 2;
wherein any aforementioned 4-10 or 4-7 membered heterocycloalkyi group optionally comprises 1 , 2, or 3 oxo substituents, wherein each oxo substituent that is present is substituted on a ring- forming carbon, nitrogen, or sulfur atom of the 4-10 or 4-7 membered heterocycloalkyi group.
In some embodiments, the present invention relates to a TPH-inhibiting compound of Formula I:
Figure imgf000015_0001
I or a pharmaceutically acceptable salt thereof, wherein:
Ring A is C3-10 cycloalkyl, Ce-io aryl, 4 to 10-membered heterocycloalkyl, or 5 to 10- membered heteroaiyl;
L is O or NR4;
W is N or CR5;
X is N or CR6;
Ύ is N or CR7;
wherein only one of X and Y is N;
R1 is H, CMO alkyl, C3-iocycloalkyl, phenyl, -(CR8R9)POC(0)R10, -(CR8R9)pNRnR12 , or -(CR8R9)pC(0)NRnR12, wherein said CM 0 alkyl, C3-to cycloalkyl, and phenyl are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from F, CI, Br, CN, C alkyl, and Ci.4 haloalkyl;
R2 and R3 are each independently selected from H, CM alkyl, and Ci-4 haloalkyl;
R4 is H or Ci.4 alkyl;
R5 and R6 are each independently selected from H, halo, and Ci-4 alkyl;
R7 is H, Ci-4 alkyl, C2-6 alkenyl, C3-io cycloalkyl, C3-io cycloalkyl-C alkyl, C6-io aryl, C6- io aryl-Ci- alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyi)-Ci alkyl, 5-10 membered heteroaiyl, (5-10 membered heteroaryl)-Ci-4 alkyl, NR,3RH, OR15, C(0)R16, S(0)qRi7, wherein said Ci-4 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C3-iocycloalkyl-Ci-4 alkyl, C6-io aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl) - Ci- alkyl, 5-10 membered heteroaiyl, and (5-10 membered heteroaryl)-Ci-4 alkyl are each optionally substituted by 1, 2, or 3 substituents selected from halo, C alkyl, C2-6 alkenyl, amino, C t -4 alky lam i no, C2-s dialkylamino, hydroxy, and Ci^ alkoxy;
R8 and R9 are each independently selected from H and C alkyl;
R10 is Ci-6 alkyl optionally substituted by 1, 2 or 3 substituents independently selected from Ci-6 haloalkyl, C3.10 cycloalkyl, ORa, and NRcRd;
R11 and Ri2 are each independently selected from H and Ci-6 alkyl;
R13 is H or Ci.4 alkyl;
RH is H, C1.4 alkyl, C3.7 cycloalkyl, C3-7 cycloalkyl-C)-4 alkyl, Ce-io aryl, C6.io aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, 5-10 membered heteroaiyl, or (5-10 membered heteroaryl)-C 1.4 alkyl, C(0)Rbl, C(0)ORal } C(0)NRcIRdI, S(0)Rbi, S(0)2Rbl, or S(0)2NRc,Rdl } wherein said CM alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-Cf.4 alkyl, Ce-ioaryl, Ce-io aryl-Cm alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-Ci-4 alkyl are each optionally substituted by 1, 2, or 3 substltuents independently selected from halo, C M alkyl, C haloalkyl, CN, N02, ORal, SRal, C(0)Rbl 5 C(0)NRclRdl, C(0)ORa\ OC(0)Rbl, OC(0)NRclRdl, NRclRd!, NRciC(0)Rbl, NRclC(0)ORal,
NRctC(0)NRc,Rdl, NRc!S(0)R l, NRCIS(0)2Rbi, NRclS(0)2NRcIRdl, S(0)Rbl, S(0)NRclRdl, S(0)2Rbl, and S(0)2NRclRdl;
or R13 and R14 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7- membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substltuents
independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, 5-6 membered heteroaryl, halo, CN, ORflt, SRal, C(0)Rbl, C(O)NR0lRdl, C(0)ORttI, OC(0)Rbl, OC(0)NRclRdl, NRclRd, 5 NRclC(0)Rbl, NRclC(0)NRc!Rdl, NRclC(0)ORat, S(0)Rbl, S(0)NRc,Rdi, S(0)2Rbl, NRclS(0)2Rbi, NRcSS(0)2NRclRdI, and S(0)2NRclRdl, wherein said Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substltuents independently selected from halo, CN, ORal, SRal, C(0)Rbl, C(0)NRoiRd! 5 C(0)ORal, OC(0)Rbl,
OC(0)NRclRd!, NRc,Rdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)ORal, S(0)Rbl,
S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbl, NRclS(0)2NRc,Rd\ and S(0)2NRclRd!;
R!5 is H, C alkyl, C3-7 cycloalkyl, C3 -7 cycloalkyl-Ci-4 alkyl, C6-io aryl, C6-io aryl-C[-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci-4 alky], 5-10 membered heteroaryl, or (5-10 membered heteroaryl )-C 1-4 alkyl, wherein said C1-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-Ci-4 alkyl, Ce-io aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered
heterocycloalkyl, (4-10 membered heterocycloalkyl) -C alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-Ci-4 alkyl are each optionally substituted by 1, 2, or 3 substltuents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, 5-6 membered heteroaryl, CN, ORal, SRaI, C(0)Rbt, C(0)NRclRdl, C(0)ORal, OC(0)Rbl,
OC(O)NR0lRdi, NRclRdl, NRc,C(0)Rbl, NRclC(0)NRo!Rtit, NRclC(0)ORal, S(0)Rbl,
S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbl, NRclS(O)2NR0lRdl, and S(0)2NRclRd!;
R16 is C1.4 alkyl or NRi8aR18b wherein said CM alkyl is optionally substituted by 1, 2, or 3 substltuents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, 5-6 membered heteroaryi, CN, ORal, SRal, C(0)Rbi, C(0)NRclRdl, C(0)ORal, OC(0)R i, OC(0)NRc,Rdl, NRc!Rdi, NR0lC(O)RbI, NRclC(0)NRclRdI, NRc!C(0)ORal, S(0)Rbl, S(0)NRclRdi, S(0)2Rbl, NRclS(0)2Rbl, NRclS(0)2NRclRdl, and S(0)2NRciRdl;
R17 is Ci-4 alkyl, NR18aR!8b, or ORISe, wherein said Ci-4 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-]o aryl, 5-6 membered heteroaryi, CN, ORal, SRal, C(0)Rbl, C(0)NRclRdt, C(0)ORal, OC(0)Rbl, OC(0)NRclRdl, NRclRdI, NRc)C(0)Rbl, NRciC(0)NRclRdl,
NR^C^OR"1, S(0)Rbl, S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbl 5 NRclS(0)2NRciRdl 5 and S(O)2NR0lRdl;
RI8a and R!8b are each independently selected from H and CM alkyl wherein said CM alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, 5-6 membered heteroaryi, CN, ORai, SRal, C(0)Rbl 5 C(0)NRclRdl, C(0)ORal, OC(0)R \ OC(0)NRclRdi, NR^R4", NRclC(0)Rb¾, NRc,C(0)NRdRdl ; NRc4C(0)ORa!, S(0)Rbl, S(0)NRclRdl, S(0)2Rbl, NRc,S(0)2R l,
NRciS(0)2NRciRdl, and S(0)2NRclRdl ;
or R18a and R'Sb together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, 5-6 membered heteroaryi, halo, CN, ORfll, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORa1, OC(0)Rbl, OC(0)NRclRd, i NR^R"1, NRclC(0)RbI, NRclC(0)NRclRdl, NRcIC(0)OR l, S(0)Rb!, S(0)NRciRdI, S(0)2Rbl, NRc,S(0)2Rbl, NRc,S(0)2NRclRdi, and S(0)2NRclRdl, wherein said Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, and 5-6 membered heteroaryi are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORal, SRa1, C(0)Rb!, C(0)NRc!Rdl J C(0)ORal, OC(0)R l,
OC(0)NRCIRdl, NRc!Rdl, NRclC(0)Rbi, NR0lC(O)NRclRdl, NR0,C(O)ORal, S(0)RbI,
S(0)NRclRdl, S(0)2Rbi, NRCIS(0)2Rbl ; NRciS(0)2NRc,Rdl, and S(0)2NRclRdl;
R is H, Cue alkyl, C3-10 cycloalkyl, C3- cycloalkyl-Ci-4 alkyl, Ce-io aryl, C6-so aryl-Ci.4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Cf. alkyl, 5-10 membered heteroaryi, or (5-10 membered heteroaryl)-C 1.4 alkyl, wherein said Ci-e alkyl, C3-7 cycloalkyl, C3-io cycloalkyl-Ci-4 alkyl, Ce-ioaryl, C6-io aryl-Ci- alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-C|.4 alkyl, 5-10 membered heteroaryi, and (5- 10 membered heteroaryl)-C|.<i alkyl are each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, CM alkyl, CM haloalkyl, CN} N02; ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl, OC(0)NRclRdl } NRciRdi, NRciC(0)Rbi, NRdC(0)ORal, NRc,C(0)NRclRdl, NRclS(0)Rb!, NRc!S(0)2Rbi, NRc,S(0)2NRclRdl, S(0)RbI, S(0)NRCIRdl, S(0)2Rbl , and S(0)2NRc,Rdl ;
RA is H, Cy1, halo, Ci-e alkyl, C2-6 alkenyl, CN, N02f OR*2, SRa2, C(0)Rb2 s C(0)NRc2Rd2, C(0)ORa2, OC(0)Rb2, OC(0)NRc R 2, NRc2Rd2, NRc C(0)R 2, NRc2C(0)ORa2,
NRc2C(0)NRc2Rd2, NRc S(0)Rb2, NRc2S(0)2Rb2, NRc S(0)2NRc2Rd2, S(0)R 2, S(0)NRc2Rd2, S(0)2R 2, or S(0)2NRc2Rd2, wherein said Ci-6 alkyl and C2.6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy1, halo, O-e alkyl, C2. 6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa2, SRa\ C(0)Rb2, C(0)NRc2Rd2, C(0)ORa2, OC(0)Rb2, OC(0)NRc2Rd2, NRc2Rd2, NRc2C(0)Rb2, NRc2C(0)ORa2, NRc C(0)NRc2Rd2, NR02S(O)Rb2, NR S(0)2Rb2, NRc S(0)2NRc2Rd2, S(0)Rb2, S(0)NRc2Rd2, S(0)2Rb2, and S(0)2NRe2Rd2;
RB is H, Cy2, halo, Ci-6 alkyl, C2.6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa3, SR 3, C(0)Rb3, C(0)NRc3Rd3, C(0)ORn3, OC(0)Rb3, 0C(0)NRc3Rd3, NRc3Rd3, NRc3C(0)Rb3, NRc3C(0)ORa3, NRc3C(0)NR 3Rd3, NRc3S(0)Rb3, NRc3S(0)2R 3, NRc3S(0)2NRc3Rd3, S(0)Rb3, S(0)NRc3Rd3, S(0)2Rb3, or S(0)2NRc3Rd3, wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from Cy2, halo, Ci-6 alkyl, C2- 6 alkenyl, Ct-6 haloalkyl, CN, N02, 0Ra3, SR33, C(0)Rb3, C(0)NRc3R 3, C(0)ORa3, OC(0)Rb3, OC(0)NRc3Rd3 ; NRc3Rd3, NRc3C(0)Rb3, NRc3C(0)0Ra3, NRc3C(0)NRc3Rd3, NRc3S(0)Rb3, NRclS(0)2Rb3, NRc3S(0)2NRc3Rd3, S(0)Rb3, S(0)NRc3Rd3, S(0)2Rb3, and S(0)2NRc3Rd3;
Rc and RD are each independently selected from H, halo, Q.e alkyl, C .6 alkenyl, Ci-6 haloalkyl, CN, N02, 0Ra4, SRa4, C(0)RM, C(0)NRc4Rd4, C(0)ORa4, OC(0)Rb4, OC^NR^R"4, NRc4Rd4, NRc4C(0)Rb4, NRc4C(0)ORa4, NRc4C(0)NRc4Rd4, NRc4S(0)Rb4, NRc4S(0)2Rb4, NRc4S(0)2NRc4Rd4, S(0)Rb4, S(0)NRc4Rd4, S(0)2 b4 ) and SfO^N ^R114 wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Ce-io aryl, C3-io cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, halo, Ci-6 alkyl, C2.6 alkenyl, Ci-6 haloalkyl, CN, N02} OR84, SRa4, C(0)Rb4, C(0)NRc4Rd4, C(0)ORa4, OC(0)Rb4, OC(0)NRc4Rd4, NRc Rd4, NRc4C(0)Rb ) NRc4C(0)ORa4, NRc4C(0)NRc Rd4 ) NRc4S(0)Rb4, NRc4S(0)2Rb4, NR^SCO^NR^R1*4, S(0)Rb4, S(0)NRc4Rd4, S(0)2Rb4, and S(0)2NRc Rd4; Cy1 and Cy2 are each independently selected from C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy;
each RCy is independently selected from halo, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, Ce-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO2, ORa5, SRa5, C(0)Rb5 s C(0)NRc5Rd5, C(0)ORa5, OC(0)Rb5 ; OC(0)NRc5Rd5, NRc5Rd\
NRc5C(0)Rb5 } NRc5C(0)ORa5, NR 5C(0)NRc5Rds, NRc5S(0)Rb5, NRc5S(0)2Rb5,
NRc5S(0)2NRc5Rds, S(0)Rb5, S(0)NRcSRdS, S(0)2Rb5, and S(0)2NRcSRd5, wherein said Ci-e alkyl, C2-6 alkenyl Ce-io ryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-β alkyl, CN, N02, ORa5, SRa5, C(0)Rb5, C(0)NRc5RdS, C(0)ORa5,
OC(0)Rb5, OC(0)NRc5Rd5, NRc5Rd5, NRc5C(0)Rb5, NRc5C(0)ORa5, NRc5C(0)NRc5Rds,
NRc5S(0)Rb5, NRc5S(0)2Rb5, NRcSS(0)2NRc5Rd5, S(0)Rb5, S(0)NRc5Rds, S(0)2Rb5, and
S(0)2NRc5Rd5;
each Ra, Ra[, Ra2, R33, Ra4, and RaS is independently selected from H, Ci-6 alkyl, C1.4 haloalkyl, C2-6 alkenyl, Ce-io aryl, C3- 10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Gs-jo aryl-C 1 -4 alkyl, C3-io cycloalkyl-Ci.4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, or (4-10 membered heterocycloalkyl)-Ci-4 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C6- to aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl- Ci-4 alkyi, C3-io cycloalkyl-C alkyl, (5-10 membered heteroaiyl)-Ci-4 alkyl, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from CM alkyl, halo, CN, OR*6, C(0)R 6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6 s OC(0)NRc6Rd6, NRe6Rd6, NRc6C(0)Rb6 } NRc6C(0)NRc6Rd6,
NRc C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
each RbI, Rb2, Rb3, Rb4, and Rbs is independently selected from H, C!-6 alkyl, C
haloalkyl, C2.6 alkenyl, C6-io aryl, C3-!o cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-io ryl-CM alkyl, Ca-te cycloalkyl-CM alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, or (4-10 membered heterocycloalky^-d^ alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C6- 10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl- C 1-4 alkyl, C3-io cycloalkyl-CM alkyl, (5-10 membered heteroaryl) -C 1- alkyl, and (4-10 membered heterocycloalkyl)-Ci.4 alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C M alkyl, halo, CN, ORa6, C(0)Rb6, C(0)NRc6Rd6, C(0)OR 6, OC(0)Rb6, OC(0)NRc6Rd6 ) NRc6Rd6 ; NRc6C(0)Rb6, NRc6C(0)NRc6Rd6 ;
NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2R 6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
each R , Rd, Rcl, Rdl, R°2, Rd2, Rc3, Rd3, Rc4, Rd4, Rc5, and RdS is independently selected from H, Ci-6 alkyl, CM haloalkyl, C2-6 alkenyl, C6-io aryl, C3-io cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-ioaryl-Ci-4 alkyl, C3-io cycloalkyl-Ci-4 alkyl, (5- 10 membered heteroaryl)-Ci-4 alkyl, or (4-10 membered heterocycloalkyl)-Ci-4 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, Ce-toaryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-io aryl-C 1.4 alkyl, C3-io cycloalkyl-C 1.4 alkyl, (5-10 membered heteroaryl)-C!-4 alkyl, and (4-10 membered heterocycloalkyl)-C[.4 alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Ci-4 alkyl, halo, CN, ORa6 ; SRa6 5 C(0)Rb6 } C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6,
NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRe6Rd6, S(0)2R 6 ;
NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, 5-6 membered heteroaryl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NR 6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6 ; NRc6C(0)R 6, NRc C(0)NRc6Rdfi, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6 } NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6 5 C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6} NRc6C(0)Rb65 NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc Rd6 } and S(0)2NRc6Rd6;
or any Rc) and Rdl together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, 5-6 membered heteroaryl, halo, CN, OR 6, SRa6, C(0)Rb6, C(0)NRe6Rd5, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRcfiC(0)R 6, NRc6C(0)NRc6Rd6 5 NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said Ci-e alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa5 5 SRa6 5 C(0)Rb6 5 C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6,
OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRe6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6,
S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2R 6 5 NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rc2 and Rd2 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, and 5-6 membered heteroaryl, Ci-ehaloalkyl, halo, CN, ORa6, SRa6, C(0)R 6 } C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc Rd6, NRc6Rd5, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6,
NRc6C(0)ORa6, S(0)Rbfi, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRe6S(0)2NRc6Rd6, and S(0) NRc6Rd6, wherein said Ci-6 alkyl, 0¾-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa5, C(0)Rb6, C(0)NRc6Rd6, C(O)0Ra6,
OC(0)R 6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRe6S(0)2Rb6 s NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rc3 and Rd3 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, Ci^ haloalkyl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6,
NRc6C(0)ORa6, S(0)Rb6, S(0)NRe6Rd6, S(0)2Rb6, NRc6S(0)2Rh6 5 NRe6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said Ci-6 alkyl, C3.7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, OR"6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORaf\
OC(0)Rb6 ; OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6 ; NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rc4 and Rd4 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from d-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, 5-6 membered heteroaiyl, Ci-6 haloalkyl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)R 6, OC(0)NRc6Rd6 ; NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd5 }
NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rbfi, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said Ci.6 alkyl, C3.7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6,
OC(0)R 6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa5, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rc5 and Rd5 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ct-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, 5-6 membered heteroaiyl, Ci-ehaloalkyl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORn5, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRe6Rd6,
NRc C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2R 6, NRc6S(0)2Rb6 5 NRe6S(0)2NRc6Rd6 5 and S(0)2NRc6Rd6, wherein said Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6,
OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6R 6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
each Ra6, Rb6, Rc6, and Rd6 is independently selected from H, CM alkyl, C2-4 alkenyl, C3.7 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein said Ci-4 alkyl, C2.4 alkenyl, C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C alkyl, C1-4 alkoxy, CM alkylthio, C alkylamino, and di(Ci-4 alkyl)amino;
n is 1 or 2;
p is 1 , 2, or 3; and
q is 1 or 2;
wherein any aforementioned 4-10 or 4-7 membered heterocycloalkyl group optionally comprises 1, 2, or 3 oxo substituents, wherein each oxo substituent that is present is substituted on a ring-forming carbon, nitrogen, or sulfur atom of the 4-10 or 4-7 membered heterocycloalkyl group.
In some embodiments, L is O.
In some embodiments, L is NR4,
in some embodiments, W is CR5; X is N; and Y is CR7.
In some embodiments, W is N; X is N; and Y is CR7,
In some embodiments, W is CR5; X is CR6; and Y is N.
In some embodiments, W is CR5; X is CR6; and Y is CR7.
In some embodiments, W is N; X is CR6; and Y is CR7,
In some embodiments, R2 is H and R3 is H.
In some embodiments, R2 is H and R3 is C alkyl,
In some embodiments, R2 is H and R3 is methyl.
In some embodiments, R2 is H and R3 is C]-4 haloalkyl.
In some embodiments, R2 is H and R3 is trifluoromethyl.
In some embodiments, is i .
In some embodiments, n is 2,
In some embodiments, R1 is H.
In some embodiments, R1 is Ci-io alkyl, Qj-io cycloalkyl, phenyl, -(CR8R9)POC(0)R10, -(CR8R9)p NRl lR'2 , or -(CR8R9)pC(0)NRnR12, wherein said CMO alkyl, C3-io cycloalkyl, and phenyl are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from F, CI, Br, CN, CM alkyl, and Ci-4 haloalkyl.
In some embodiments, R1 is Ci-io alkyl.
In some embodiments, R1 is ethyl.
In some embodiments, R4 is H.
In some embodiments, R5 is H.
In some embodiments, R6 is H.
In some embodiments, R7 is other than H.
In some embodiments, R7 is C alkyl, NR,3R^ or OR15
In some embodiments, R7 is NRt3RH.
In some embodiments, R7 is NH2.
In some embodiments, R7 is CM alkyl. In some embodiments, R7 is OR15.
In some embodiments, Ring A is C3-iocycloalkyl.
In some embodiments, Ring A is Ce-io aryl.
In some embodiments, Ring A is phenyl.
In some embodiments, Ring A is 4 to 10-membered heterocycloalkyl.
In some embodiments, Ring A is phenyl, adamantanyl, naphthyl, 1,2,3,4- tetrahydroquinoxalinyl, 3,4-dihydroqinazolinyl, 1,2,3,4-tetrahydiOquinazolinyl, or pyridyl.
In some embodiments, Ring A is 5 to 10-membered heteroaryl,
In some embodiments, at least one of RA, RB, Rc, and RD is other than hydrogen.
In some embodiments, at least two of RA, RB, Rc, and RD are other than hydrogen.
In some embodiments, RA is Cy1.
In some embodiments, RA is Ce-io aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.
In some embodiments, RA is 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.
In some embodiments, RA is 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
In some embodiments, RA is pyrazolyl which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.
In some embodiments, RA is 3 -methyl- lH-pyrazol-1 -yl.
In some embodiments, RA is C6-toaryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
In some embodiments, RA is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
In some embodiments, RB is H.
In some embodiments, RB is Cy2, halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, N02, ORe3, SR33, C(0)Rb3, C(0)NRc3Rd3 ; C(0)ORa3, OC(0)Rb3, OC(0)NRc3Rd3, NRc3Rd3,
NRc3C(0)Rb3, NRc3C(0)ORa3, NRc3C(0)NRc3Rd3, NRc3S(0)Rb3, NRc3S(0)2Rb3,
NRc3S(0)2NRc3Rd3, S(0)Rb3, S(0)NRc3Rd3, S(0)2Rb3, and S(0)2NRc3Rd3 ; wherein said Ct-6 alkyl and C2.6 alkenyl are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from Cy2, halo, Ci-6 alkyl, C2.6 alkenyl, Ci-e haloalkyl, CN, N02, ORa3, SR83, C(0)Rb3, C(0)NRc3Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRe3Rd3, NRc3Rd3, NRc3C(0)Rb3, NR^CCC OR83, NRc C(0)NRc3Rd3, NRc3S(0)Rb3, NRclS(0)2Rb3 s NRc3S(0)2NRc3Rd3, S(0)Rb3, S(0)NRc3Rd3, S(0)2R 3, and S(0)2NRc3Rd3.
In some embodiments, RB is Cy2.
In some embodiments, RB is C6-io aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1 , 2, 3, 4, or 5 substituents independently selected from RCy.
In some embodiments, RB is halo, Ci-e alkyl, C2-6 alkenyl, O-e haloalkyl, CN, N02, ORa3, SR*3, C(0)Rb3, C(0)NRc3Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc3Rd3, NRc3Rd3, NRc3C(0)Rb3, NR^C-JOR33, NRc3C(0)NRc3Rd3, NRc3S(0)Rb3, NRc3S(0)2Rb3 5 NRc3S(0)2NRc3Rd3, S(0)Rb3, S(0)NRo3Rd3, S(0)2R 3 , and S(0)2NRc3Rd3, wherein said C i .6 alkyl and C2.6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy2, halo, Ci- 6 alkyl, C2.6 alkenyl, Ci_6 haloalkyl, CN, N02j OR33, SRa3, C(0)Rb3, C(0)NRc3Rd3, CCC OR*3, OC(0)R 3, OC(0)NRc3Rd3, NRc3Rd3, NRc3C(0)Rb3, NRc3C(0)ORa3, NRc3C(0)NRc3Rd3 5
NRc3S(0)Rb3, NRclS(0)2Rb3, NRc3S(0)2NRc3Rd3, S(0)Rb3, S(0)NRc3Rd ; S(0)2Rb3, and
S(0)2NRc3Rd3.
In some embodiments, RB is halo.
In some embodiments, Rc is H.
In some embodiments, Rc is halo, Ci-c alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, N02, OR 4, SRa4, C(0)Rb4 > C(0)NRc4Rd4, C(0)ORa4, OC(0)Rb4, OC(0)NRc4Rd4, NR^R^, NRc C(0)Rb4 ) NRc4C(0)ORa4, N ^C NR^4, NRc4S(0)Rb4, NRc S(0)2Rb ) NRc S(0)2NRc Rd4, S(0)Rb4, S(0)NRc4Rd4, S(0)2RM, and S(0)2NRc4Rd4; wherein said Ci-6 aikyl and C2-6 alkenyl are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from C6-ioaryl, C3- i0cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, Cf-6 alkyl, C2.6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa4, SRa4, C(0)Rb4, C(0)NRc4Rd4, C(0)ORa4, 0C(O)Rb ) OC(0)NRc4Rd4, NR^R114, NRc4C(0)Rb4, NRc C(0)ORa4, NRc C(0)NRc Rd4, NRc4S(0)Rb4, NRc4S(0)2Rb4, NRc S(0)2NRc Rd J S(0)Rb4, S(0)NRc Rd > S(0)2RM, and S(0)2NRc4Rd4.
In some embodiments, RD is H,
In some embodiments, RD is halo, Ci-6 alkyi, C2.6 alkenyl, Cj-6 haloalkyl, CN, N02, ORa4, SRa4, C(0)Rb4, C(0)NRc4Rd4, C(0)ORn4 5 OC(0)Rb4, OC(0)NRc4Rd4, NR^R114, NRc C(0)Rb4 J NRc4C(0)ORa4, NRc C(0)NRc Rd4, NRc4S(0)Rb4, NRc4S(0)2Rb4, NRo4S(0)2NRc4Rd4, S(0)Rb4, S(0)NRc4Rd4, S(0)2Rb4, and S(0)2NRc4Rd4; wherein said Ci-6 alkyi and C2.6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C6.io aryl, C3- io cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa4, SRa4, C(0)Rb4, C(0)NRc4Rd4, C(0)ORa4, OC(0)R 4, OC(0)NRc4Rd 5 NR^R*14, NRc4C(0)R 4, NRc C(0)ORa4, NRc C(0)NRc Rd4, NRc S(0}RM, NR^O)^4, NRc4S(0)2NRc Rd4, S(0)Rb4, S(0)NRc Rd4, S(0)2Rb4, and S(0)2NRc4Rd4.
In some e Ha:
Figure imgf000027_0001
In some embodiments, the compounds of the invention have Formula lib:
Figure imgf000027_0002
In some embodiments, the compounds of the invention have Formula lie:
Figure imgf000028_0001
He.
In some embodiments, where the compounds of the invention have Formula Ila, lib, lie, lid, or lie, L is O,
In some embodiments, where the compounds of the invention have Formula Ila, lib, lie, lid, or IIe, L is NR4.
In some embodiments, where the compounds of the invention have Formula Ila, lib, lie, Ild, or He, R3 is H.
In some embodiments, where the compounds of the invention have Formula Ila, lib, lie, Ild, or He, R2 is CF3 and R3 is H.
In some embodiments, where the compounds of the invention have Formula Ila, lib, lie, Ild, or lie, R! is H or Ci-io alkyl.
In some embodiments, where the compounds of the invention have Formula Ila, lib, lie, Hd, o IIe, RA is Cy1.
In some embodiments, where the compounds of the invention have Formula Ila, lib, lie,
Ild, or lie, RA is C6-io aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1 , 2, 3, 4, or 5 substituents independently selected from RCy.
In some embodiments, where the compounds of the invention have Formula Ila, lib, He, Ild, or He, RA is 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.
In some embodiments, where the compounds of the invention have Formula Ila, lib, lie, Ild, or He, RA is 5 to 6-membered heteroaryl optionally substituted by 1 , 2, or 3 substituents independently selected from RCy.
In some embodiments, where the compounds of the invention have Formula Ila, lib, lie, Ild, or He, RA is Ce-io aryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy
In some embodiments, where the compounds of the invention have Formula Ila, lib, lie, Ild, or lie, RA is phenyl optionally substituted by 1 , 2, or 3 substituents independently selected from RCy.
In some embodiments, where the compounds of the invention have Formula Ila, lib, lie,
Ild, or He, RB is Cy2. In some embodiments, where the compounds of the invention have Formula Ila, lib, lie, lid, or He, RB is H, halo, Ci-e alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, ORa3, C(0)NRc3Rd3 5 or C(0)ORa3, wherein said Ci.6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci-6 haloalkyl, CN, N02; OR33, SR83, C(0)Rb3, C(0)NRc3Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc3Rd3 ; NRc3Rd3 5 NRc3C(0)Rb3, NRc3C(0)ORa3 } NRc3C(0)NRc3Rd3, NRc3S(0)Rb3, NRclS(0)2Rb3, NRc3S(0)2NRc3Rd3, S(0)Rb3, S(0)NRc3Rd3, S(0)2Rb3, and S(0)2NRc3Rd3.
In some embodiments, where the compounds of the invention have Formula Ila, lib, lie, lid, or He, Rc is H.
In some embodiments, where the compounds of the invention have Formula Ila, lib, He,
Hd, or He, RD is H.
In some embodiments, where the compounds of the invention have Formula Ila, lib, He, lid, or lie, R5 is H.
In some embodiments, where the compounds of the invention have Formula Ila, lib, lie, lid, or He, R6 is H,
In some embodiments, the compounds of the invention have Formula Ilia or Ilib:
Figure imgf000030_0001
Ilia
Figure imgf000031_0001
Illb.
In some embodiments, where the compounds of the invention have Formula Ilia or Illb, R2 is CF3.
In some embodiments, where the compounds of the invention have Formula Ilia or Illb,
R1 is H or Ci-io alkyl.
In some embodiments, where the compounds of the invention have Formula Ilia or Illb, RA is Cy'.
In some embodiments, where the compounds of the invention have Formula Ilia or Illb, RA is C6-ioaryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.
In some embodiments, where the compounds of the invention have Formula Ilia or Illb, RA is 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.
In some embodiments, where the compounds of the invention have Formula Ilia or Illb,
RA is 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
In some embodiments, where the compounds of the invention have Formula Ilia or Illb, RA is Ce-io ryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
In some embodiments, where the compounds of the invention have Formula Ilia or Illb,
RA is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
In some embodiments, where the compounds of the invention have Formula Ilia or Illb, RB is Cy2. In some embodiments, where the compounds of the invention have Formula Ilia or Illb, RB is H, halo, Ci.6 alkyl, C2-6 alkenyl, Ci-e haloalkyl, CN, ORa3 ; C(0)NRc Rd3 } or C(0)ORa3, wherein said C]-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3
substituents independently selected from halo, Ci-6 haloalkyl, CN, NC% ORa3 } SR*3, C(0)Rb3 ; C(0)NRc3Rd3, C(0)ORi'3, OC(0)Rb3, OC(0)NRc3Rd3, NRc3Rd3 ; NRc3C(0)Rb3, NRc C(0)ORa3, NRc3C(0)NRc3Rd3 ; NRc3S(0)Rb3 ; NRclS(0)2Rb3, NRc3S(0)2NRc3Rd3, S(0)Rb3, S(0)NRc3Rd3, S(0)2Rb3, and S(0)2NRc3Rd3.
In some embodiments, where the compounds of the invention have Formula Ilia or Illb, Rc is H.
In some embodiments, where the compounds of the invention have Formula Ilia or Illb,
RD is H.
In some embodiments, the compounds of the invention have Formula IV:
Figure imgf000032_0001
IV.
In some embodiments, where the compounds of the invention have Formula IV, R2 is
CF3.
In some embodiments, where the compounds of the invention have Formula IV, R1 is H or Ci-io alkyl.
In some embodiments, where the compounds of the invention have Formula IV, RA is Cy1.
In some embodiments, where the compounds of the invention have Formula IV, RA is C6- lo ryi or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy, In some embodiments, where the compounds of the invention have Formula IV, RA is 5- 10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy,
In some embodiments, where the compounds of the invention have Formula IV, RA is 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from Rc>'.
In some embodiments, where the compounds of the invention have Formula IV, RA is Ce- lo aryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
In some embodiments, where the compounds of the invention have Formula IV, RA is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
In some embodiments, where the compounds of the invention have Formula IV, RB is
Cy2.
In some embodiments, where the compounds of the invention have Formula IV, RQ is H, halo, Ct-6 alkyl, C2-6 alkenyl, Cue haloalkyl, CN, OR*3, C(0)NRc3Rd3, or C(0)ORa3, wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci-6 haloalkyl, CN, N02, ORa3, SRa3, C(0)Rb3, C(0)NRc3Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc3Rd3, NRc3Rd3, NRc3C(0)Rb3, NRc3C(0)ORa3,
NRc3C(0)NRc3Rd3, NRc3S(0)Rb3, NRdS(0)2Rb3, NRc3S(0)2NRc3Rd3, S(0)RM, S(0)NRc3Rd3, S(0)2Rb3 s and S(0)2NRc3Rd3.
In some embodiments, where the compounds of the invention have Formula IV, Rc is H.
In some embodiments, where the compounds of the invention have Formula IV, RD is H, In some embodiments, the compounds of the invention have Formula Va:
Figure imgf000033_0001
Va.
In some embodiments, where the compounds of the invention have Formula Va, R2 is
CF3.
In some embodiments, where the compounds of the invention have Formula Va, R1 is H or Ci-io alkyl.
In some embodiments, where the compounds of the invention have Formula Va, RA is
Cy!.
In some embodiments, where the compounds of the invention have Formula Va, RA is C6- loaryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.
In some embodiments, where the compounds of the invention have Formula Va, RA is 5- 10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy,
In some embodiments, where the compounds of the invention have Formula Va, RA is 5 to 6-membered heteroaryl optionally substituted by 1 , 2, or 3 substituents independently selected from RC
In some embodiments, where the compounds of the invention have Formula Va, RA is C6- lo aryl optionally substituted by 1 , 2, or 3 substituents independently selected from RCy.
In some embodiments, where the compounds of the invention have Formula Va, RA is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
In some embodiments, where the compounds of the invention have Formula Va, RB is
Cy2.
In some embodiments, where the compounds of the invention have Formula Va, RB is H, halo, Ci-6 alkyl, C2.6 alkenyl, CJ-6 haloalkyl, CN, ORa3, C(0)NRc3Rd3, or C(0)ORfl3, wherein said Ci-6 alkyl and C2.6 alkenyl are each optionally substituted with 1 , 2, or 3 substituents independently selected from halo, Ci-6 haloalkyl, CN, N02; ORa3, SRa3, C(0)R 3, C(0)NRc3Rd3 5 C(0)ORa3, OC(0)Rb3, OC(0)NRc3Rd3, NRc3Rd3, NRc3C(0)Rb3, R^C^OR83,
NRc C(0)NRc3Rd3, NRo3S(0)Rb3, NRclS(0)2Rb3, NRc3S(0)2NRe3Rd3, S(0)R 3, S(0)NRc3Rd3, S(0)2Rb3, and S(0)2NRc3Rd3,
In some embodiments, the compounds of the invention have Formula Vb:
Figure imgf000035_0001
Vb.
In some embodiments, where the compounds of the invention have Formula Vb, R2 is
CF3.
In some embodiments, where the compounds of the invention have Formula Vb, R! is H or Ci-io alkyl.
In some embodiments, where the compounds of the invention have Formula Vb, RA is
Cys.
In some embodiments, where the compounds of the invention have Formula Vb, RA is C6- io aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1 , 2, 3, 4, or 5 substituents independently selected from RCy.
In some embodiments, where the compounds of the invention have Formula Vb, RA is 5- 10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R^'.
In some embodiments, where the compounds of the invention have Formula Vb, RA is 5 to 6-membered heteroaryl optionally substituted by 1 , 2, or 3 substituents independently selected from RCy.
In some embodiments, where the compounds of the invention have Formula Vb, RA is C6- io aryl optionally substituted by 1, 2, or 3 substituents independently selected from
In some embodiments, where the compounds of the invention have Formula Vb, RA is phenyl optionally substituted by 1 , 2, or 3 substituents independently selected from
In some embodiments, where the compounds of the invention have Formula Vb, RB is
Cy2. In some embodiments, where the compounds of the invention have Formula Vb, RB is H, halo, Ci-6 alkyl, C2.6 alkenyl, Ci-6 haloalkyl, CN; ORa3, C(0)NRe3Rd3, or C(0)ORa3, wherein said Ci-6 alkyl and C2.6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci-e haloalkyl, CN, N02, ORa3, SRa3, C(0)Rb3, C(0)NRc3Rd3, C(0)ORa3, OC(0)Rw, OC(0)NRc3Rd3, NRc3Rd3, NRc3C(0)Rb3, NRe3C(0)ORa3,
NRc3C(0)NRe3Rd3, NRc S(0)Rb3, NRclS(0)2Rb3, NRc3S(0)2NRc R 3, S(0)Rb3, S(0)NRc3Rd3, S(0)2Rb3, and S(0)2NRc3Rd3.
In some embodiments, the compounds of the invention have Formula VI:
Figure imgf000036_0001
In some embodiments, where the compounds of the invention have Formula VI, R2 is
CF3.
In some embodiments, where the compounds of the invention have Formula VI, R1 is II or Ci-to alkyl.
In some embodiments, where the compounds of the invention have Formula VI, RB is
Cy2.
In some embodiments, where the compounds of the invention have Formula VI, Cy2 is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
In some embodiments, where the compounds of the invention have Formula VI, RB is H, halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, ORa3, C(0)NRc3Rd3, or C(0)ORa3, wherein said Ci-6 alkyl and C2.6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci-6 haloalkyl, CN, N02> ORa3, SRa3, C(0)Rb\ C(0)NRc3Rd3 } C(0)ORa3, OC(0)Rb3 ; OC(0)NRc3Rd3, NRc3Rd3, NRc3C(0)Rb3, NRc3C(0)ORa3,
NRc3C(0)NRc3Rd3, NRc3S(0)Rb3, NRctS(0)2Rb3, NRc3S(0)2NRc3Rd3, S(0)Rb3, S(0)NRc3Rd3, S(0)2Rb3, and S(0)2NRc3Rd3.
In some embodiments, where the compounds of the invention have Formula VI, Rc is H,
In some embodiments, where the compounds of the invention have Formula VI, RD is H.
In some embodiments, the compounds of the invention have Formula VIA:
Figure imgf000037_0001
In some embodiments, where the compounds of the invention have Formula VIA, R2 is
CF3.
In some embodiments, where the compounds of the invention have Formula VIA, R1 is H or Cj-io alkyl.
In some embodiments, where the compounds of the invention have Formula VIA, RB is
Cy2,
In some embodiments, where the compounds of the invention have Formula VIA, Cy2 is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from RCy,
In some embodiments, where the compounds of the invention have Formula VIA, RB is H, halo, Ci-6 alkyl, C2.6 alkenyl, Ci-6 haloalkyl, CN, OR83, C(0)NRc3Rd\ or C(0)ORa3, wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci-6 haloalkyl, CN, N02, ORa3, SRa3, C(0)Rb3, C(0)NRc3Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc3Rd3, NRo3Rd3, NRe3C(0)Rb3 } NRc3C(0)ORa3, NRc3C(0)NRc3Rd3, NRc3S(0)Rb3, NRclS(0)2Rb3, NRc3S(0)2NRc3Rd3, S(0)Rb3 } S(0)NRc3Rd3, S(0)2Rb3 5 and S(0)2NRc3Rd3.
In some embodiments, the compounds of the invention have Formula VII:
Figure imgf000038_0001
wherein a is 0, 1, 2, or 3.
In some embodiments, where the compounds of the invention have Formula VII, R2 is
CF3.
In some embodiments, where the compounds of the invention have Formula VII, R! is H or Ci-io alkyl.
In some embodiments, where the compounds of the invention have Formula VII, RB is
Cy2.
In some embodiments, where the compounds of the invention have Formula VII, RB is H, halo, Ci-6 alk l, C2-6 alkenyl, Ci-6 haloalkyl, CN, ORa3, C(0)NRc3R<t3, or C(0)ORa3, wherein said Ci-6 alkyl and C2.6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C|.6 haloalkyl, CN, N02, ORa3, SRa3, C(0)Rb3, C(0)NRc3Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc3Rd3, NRc3Rd3, NRc3C(0)Rb3, NRc3C(0)ORa3,
NRc3C(0)NRc Rd3, NRc3S(0)Rb3, NRclS(0)2Rb3, NRc3S(0)2NRc3Rd3, S(0)R 3, S(0)NRc3Rd3, S(0)2Rb3, and S(0)2NRc3Rd3.
In some embodiments, where the compounds of the invention have Formula VII, RB is H or halo. In some embodiments, where the compounds of the invention have Formula VII, RB is halo.
In some embodiments, where the compounds of the invention have Formula VII, Rc is H.
In some embodiments, where the compounds of the invention have Formula VII, RD is H.
In some embodiments, where the compounds of the invention have Formula VII, RCy is halo, Ci-6 alkyl, Ci-6 haloalkyl, 4-10 membered heterocycloalkyl, CN, N02) ORaS, SRaS, C(0)Rb5, C(0)NRc5Rd5, C(0)ORaS, NRcSRds, S(0)2Rb5, and S(0)2NRc5Rd5, wherein said Ci-6 alkyl and 4- 10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, CN, N02, ORa5, SRa5, C(0)Rb5, C(0)NRc5RdS, C(0)ORa5, OC(0)Rb5, OC(0)NRc5Rd5, NRc5Rd5, NRc5C(0)R 5, NRc5C(0)ORa5,
NRc5C(0)NRc5Rd5 5 NRcSS(0)Rb5, NRc5S(0)2Rb5, NRc5S(0)2NRc5Rd5, S(0)R 5, S(0)NRcSRd5, S(0)2Rb5, and S(0)2NRc5Rd5.
In some I:
Figure imgf000039_0001
wherein a is 0, 1, 2, or 3.
In some embodiments, where the compounds of the invention have Formula VIII, R2 is
CF3.
In some embodiments, where the compounds of the invention have Formula VIII, R1 is H or Ci-io alkyl.
In some embodiments, where the compounds of the invention have Formula VIII, RB is
Cy2. In some embodiments, where the compounds of the invention have Formula VIII, RB is H, halo, Ci-6 alkyl, C2.6 alkenyl, Ci-6 haioalkyl, CN, ORa3, C(0)NRc3Rd3, or C(0)ORa3, wherein said C].6 alkyl and C2.6 alkenyl are each optionally substituted with 1 , 2, or 3 substituents independently selected from halo, Ci.6 haioalkyl, CN, N02, ORa3, SRa3, C(0)Rb3, C(0)NRc3Rd3, C(0)ORa3 } OC(0)Rb3, OC(0)NRc3Rd3, NRe3Rd3 ; NRc3C(0)Rb3, NRc3C(0)ORa3,
NRc3C(0)NRc3Rd3, NRc3S(0)Rb3, NRclS(0)2Rb3, NRc3S(0)2NRc3Rd3, S(0)Rb3, S(0)NRc3Rd3, S(0)2Rb3, and S(0)2NRc Rd3.
In some embodiments, where the compounds of the invention have Formula VIII, RB is H or halo.
In some embodiments, where the compounds of the invention have Formula VIII, RB is halo.
In some embodiments, where the compounds of the invention have Formula VIII, Rc is
H.
In some embodiments, where the compounds of the invention have Formula VIII, RD is H.
In some embodiments, where the compounds of the invention some embodiments have Formula VIII, RCy is halo, Ci-6 alkyl, Ci-e haioalkyl, 4-10 membered heterocycloalkyl, CN, N02, OR85, SRa5, C(0)Rb5, C(0)NRcSRd5, C(0)ORaS, NRc5Rd5 ( S(0)2RbS, and S(0)2NRc5Rd5, wherein said Ct-6 alkyl and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, CN, N02, OR"5, SRa5, C(0)Rb5, C(0)NRcSRds, C(0)ORa5, OC(0)Rb5, OC(0)NRcSRds, NRc5Rd5, NRc5C(0)Rb5, NRcSC(0)ORa5, NRc5C(0)NRc5Rd5, NRc5S(0)Rb5, NRc5S(0)2Rb5, NRc5S(0)2NRc5Rd5, S(0)R 5, S(0)NRc5Rd5, S(0)2Rb5, and S(0)2NRc5Rd5.
In some embodiments, where the compounds of the invention have Formula VIII, a is 0. In some embodiments, the chiral carbon to which -C(0)OR' is attached has an S configuration.
In some embodiments, the carbon to which -R2 is attached is chiral and has an R configuration.
It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination,
The term "substituted" means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group. The hydrogen atom is formally removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. The term "optionally substituted" means unsubstituted or substituted. The substituents are independently selected, and substitution may be at any chemically accessible position. It is to be understood that substitution at a given atom is limited by valency. Throughout the definitions, the term "Ci-j" indicates a range which includes the endpoints, wherein i and j are integers and indicate the number of carbons, Examples include CM, Ci-6, and the like.
The term "n-membered" where n is an integer typically describes the number of ring- forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazoiyl is an example of a 5- membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1, 2, 3, 4- tetrahydro-naphthalene is an example of a 10-membered cycioalkyl group.
At various places in the present specification various aryl, heteroaryl, cycioalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency. For example, the term "a pyridine ring" or "pyridinyl" may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.
For compounds of the invention in which a variable appears more than once, each variable can be a different moiety independently selected from the group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound, the two R groups can represent different moieties independently selected from the group defined for R,
As used herein, the term "Cj-j alkyl," employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having i to j carbon atoms. In some embodiments, the alkyl group contains from 1 to 10, 1 to 6, 1 to 4, or from 1 to 3 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, and t-butyl.
As used herein, the term "Ci-j alkoxy," employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group has i to j carbon atoms, Example alkoxy groups include methoxy, ethoxy, and propoxy (e.g., n-propoxy and isopropoxy). In some embodiments, the alkyl group has 1 to 3 carbon atoms or 1 to 4 carbon atoms.
As used herein, "Ci-j alkenyl" refers to an alkyl group having one or more double carbon- carbon bonds and having i to j carbon atoms. In some embodiments, the alkenyl moiety contains 2 to 6 or to 2 to 4 carbon atoms. Example alkenyl groups include, but are not limited to, ethenyl, /7-propenyl, isopropenyl, w-butenyl, seobutenyl, and the like.
As used herein, the term "Ci-j alkylamino" refers to a group of formula -NH(alkyl), wherein the alkyl group has i to j carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
As used herein, the term "di-Ci-j-alkylamino" refers to a group of formula -N(alkyl)2j wherein the two alkyl groups each has, independently, i to j carbon atoms. In some
embodiments, each alkyl group independently has 1 to 6 or 1 to 4 carbon atoms.
As used herein, the term "thio" refers to a group of formula -SH.
As used herein, the term "Cj.j alkylthio" refers to a group of formula -S-alkyl, wherein the alkyl group has ί to j carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
As used herein, the term "amino" refers to a group of formula -NH2.
As used herein, the term " Cj.j aryl," employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbon having i to j ring-forming carbon atoms, such as, but not limited to, phenyl, 1-naphthyl, 2- naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, aryl is C6-io aryl. In some embodiments, the aryl group is a naphthalene ring or phenyl ring. In some embodiments, the aryl group is phenyl.
As used herein, the term "arylalkyl" refers to a group of formula -Ci-j alkyl— (Cj.j aryl). In some embodiments, arylalkyl is C6-io atyl-Ci-3 alkyl. In some embodiments, arylalkyl is C6-io aryl-Ci-4 alkyl. In some embodiments, arylalkyl is benzyl.
As used herein, the term "carbonyl," employed alone or in combination with other terms, refers to a -C(=0)- group.
As used herein, the term "carboxy" refers to a group of formula -C(:=0)OH.
As used herein, the term "Cj.j cycloalkyl," employed alone or in combination with other terms, refers to a non-aromatic cyclic hydrocarbon moiety having i to j ring-forming carbon atoms, which may optionally contain one or more alkenylene groups as part of the ring structure. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings (aryl or heteroaryl) fused to the cycloalkyl ring, for example, benzo or pyrido derivatives of cyclopentane, cyclopentene, cyclohexane, and the like. Where the cycloalkyl group includes a fused aromatic ring, the cycloalkyl group can be attached at either an atom in the aromatic or non-aromatic portion. One or more ring-forming carbon atoms of a cycloalkyl group can be oxidized to form carbonyl linkages. In some embodiments, cycloalkyl is C3-10 or C3-7 cycloalkyl, which can be monocyclic or polycyclic. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyi, adamantanyl and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
As used herein, the term "cycloalkylalkyl" refers to a group of formula -Cj.j alkyl— (Ci-j cycloalkyl). In some embodiments, cycloalkylalkyl is C3-7 cycloalkyl-Ci-3 alkyl, wherein the cycloalkyl portion is monocyclic. In some embodiments, cycloalkylalkyl is C3-7 cycloalkyl-Ci-4 alkyl.
As used herein, "Ci-j haloalkoxy" refers to a group of formula -O-haloalkyl having i to j carbon atoms. An example haloalkoxy group is OCF3. An additional example haloalkoxy group is OCHF2. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
As used herein, the term "halo" refers to a halogen atom selected from F, CI, I or Br. In some embodiments, "halo" refers to a halogen atom selected from F, CI, or Br. In some embodiments, the halo group is F,
As used herein, the term "Ci-j haloalkyl," employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+l halogen atoms which may be the same or different, where "s" is the number of carbon atoms in the alkyl group, wherein the alkyl group has i to j carbon atoms. In some embodiments, the haloalkyl group is fluoromethyl, difluoromethyl, or trifluoromethyl. In some embodiments, the haloalkyl group is trifluoromethyl. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms.
As used herein, the term "heteroaryl," employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic moiety, having one or more heteroatom ring members selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl ring, which is monocyclic or bicyclic and which has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl ring, which is monocyclic and which has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in the ring(s) of the heteroaryl group can be oxidized to form N-oxides. Example heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, azolyl, oxazole, thiazole, imidazole, furan, thiophene, quinoline, isoquinoline, indole, benzothiophene, benzofuran, benzisoxazole, imidazo[l ,2-Z>]thiazole, purine, and the like.
A 5-membered heteroaryl is a heteroaryl group having five ring-forming atoms comprising carbon and one or more {e.g., 1, 2, or 3) ring atoms independently selected from N, 0, and S. Example five-membered heteroaryls include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3- thiadiazolyl, 1 ,2,3-oxadiazolyl, 1,2,4-triazolyl, 1 ,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4- triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.
A six-membered heteroaryl is a heteroaryl group having six ring-forming atoms wherein one or more {e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Example six-membered heteroaryls include pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.
As used herein, the term "heteroarylalkyl" refers to a group of formula -Ci-j alkyl-
(heteroaryi). In some embodiments, heteroarylalkyl 5-10 membered
Figure imgf000044_0001
alkyl, wherein the heteroaryl portion is monocyclic or bicyclic and lias 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroarylalkyl is 5-6 membered heteteiOaryl-Ci-3 alkyl or 5-6 membered heteteroaryl-Ci.4 alkyl, wherein the heteroaryl portion is monocyclic and has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
As used herein, the term "heterocycloalkyl," employed alone or in combination with other terms, refers to a non-aromatic ring or ring system, which optionally contains one or more alkenylene groups as part of the ring structure, and which has at least one heteroatom ring member independently selected from nitrogen, sulfur and oxygen. When the heterocycloalkyl groups contains more than one heteroatom, the heteroatoms may be the same or different. Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems, including spiro systems. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings (aryl or heteroaryl) fused to the non-aromatic ring, for example, 1,2,3,4-tetrahydro-quinoline, dihydrobenzofuran and the like. Where the
heterocycloalkyl group includes a fused aromatic ring, the heterocycloalkyl group can be attached at either an atom in the aromatic or non-aromatic portion. The carbon atoms or heteroatoms in the ring(s) of the heterocycloalkyl group can be oxidized (e.g. have one or two oxo substituents) to form a carbonyl, or sulfonyl group (or other oxidized linkage) or a nitrogen atom can be quaternized. In some embodiments, the heterocycloalkyl group is 5- to 10- membered, which can be monocyclic or bicyclic and which has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heterocycloalkyl group is 5- to 6-membered or 5- to 7-membered, Examples of heterocycloalkyl groups include 1, 2, 3, 4-tetrahydroquinoline, dihydrobenzofuran, azetidine, azepane,
pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, and pyran. Further examples of heterocycloalkyl groups include 2-oxotetrahydrofuranyl, 2-oxopyrrolidinyl, 2-oxoimidazolidinyI, 1 -oxo-1 ,2,3}4-tetrahydiOisoquinolin-6-yl, and 2-oxo-l ,3-dioxolan-4-yl.
As used herein, the term "heterocycloalkylalkyl" refers to a group of formula -Ci-j aikyl- (heterocycloalkyl). In some embodiments, heterocycloalkylalkyl is 5-10 membered
heterocycloalkyl-Ci-3 alkyl or 5-10 membered heterocycloalkyl-Ci- alkyl, wherein the heterocycloalkyl portion is monocyclic or bicyclic and has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments,
heterocycloalkylalkyl is 5-6 membered heterocycloalkyl-Ci-4 alkyl wherein the heterocycloalkyl portion is monocyclic and has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereoisomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention may be isolated as a mixture of isomers or as separated isomeric forms.
Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of -methylbenzylamine (e.g., S and R forms, or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine,
1 ,2-diaminocyclohexane, and the like.
Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.
Compounds of the invention can also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adj cent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1, 2, 4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole.
Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds, isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.
The term "compound," as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified. Compounds herein identified by name or structure without specifying the particular configuration of a stereocenter are meant to encompass all the possible configurations at the stereocenter, For example, if a particular stereocenter in a compound of the invention could be R or S, but the name or structure of the compound does not designate which it is, than the stereocenter can be either R or S.
Ail compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated.
In some embodiments, the compounds of the invention, or salts thereof, are substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compounds of the invention, Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The expressions, "ambient temperature" and "room temperature," as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a
temperature from about 20 °C to about 30 °C.
The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, EtOAc, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitiile (CH3CN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et a!., J. Pharm. Sci,, 1977, 66(1), 1-19, and in Stahl et al, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002).
The below Table is a key to some abbreviations used throughout.
Abbreviations
aim atmosphere
BOC tert-butyi-oxy-carbonyl
CAS# Chemical Abstract Service registry number
CBS Corey-B akshi - Shibata (catalyst)
CH3CN Acetonitiile
CBZ Carbobenzyioxy
DIPEA N5N-diisopropylethylamine
DMAP 4 - dimethylaminopyridi ne
DME dimethylether
DMF dimethyl formamide
dppf 1 , 1 '-bis(dipheiiylphosphino)ferrocene
EDCI l~ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
ee enantiomeric excess
EtOAc ethyl acetate
h hour(s)
min minute(s)
HOAT 1 -hyd oxy-7-azabenzotriazole
HOAc acetic acid
HPLC high-performance liquid chromatography KOAc potassium acetate
LAH lithium aluminum hydride
LDA lithium diisopropylamide
mCPBA 3-meta-chloropeiOxybenzoic acid
MeOH Methanol
MS mass spectrometry
MTBE methyl t-butyl ether
NH4OH ammonium hydroxide
NMP 1 -methyl -2 -pyrrolidone
PAH pulmonary arterial hypertension
PE petroleum ether
PheOH phenylalanine hydroxylase
Prep-TLC preparative thin-layer chromatography
p-TSA para-toluene sulfonic acid
RT room temperature
SNAr nucleophilic aromatic substitution
TBAF tetrabutylammonium fluoride
tBuOH tert-butanol
TBTU O-Cbenzotriazol-l-ylJ-N^jN^N'-tetramethyl onium tetrafluoi borate
TEA Triethylamine
TFA trifluoroacetic acid
TH tyrosine hydroxylase
TI-IF Tetrahydrofuran
TLC thin-layer chromatography
TMS Trimethylsiiyl
TMSI Trimethylsilyl iodide
TPH tryptophan hydroxylase
Synthesis,
Procedures for making compounds described herein are provided below with reference to Schemes 1-10. Optimum reaction conditions and reaction times may vary depending on the particular reactants used. Unless otherwise specified, solvents, temperatures, pressures and other reaction conditions are readily selected by one of ordinary skill in the art. Specific procedures are provided in the Examples section. Compounds are named using the "structure to name" function included in ChemDraw® v.12 (Perkin-Ehner).
Typically, reaction progress may be monitored by thin layer chromatography (TLC) or
HPLC-MS if desired. Intermediates and products may be purified by chromatography on silica gel, recrystalHzation, HPLC and/or reverse phase HPLC. In the reactions described below, it may be necessary to protect reactive functional groups (such as hydroxy, amino, thio, or carboxy groups) to avoid their unwanted participation in the reactions. The incorporation of such groups, and the methods required to introduce and remove them are known to those skilled in the art (for example, see Greene, Wuts, Protective Groups in Organic Synthesis. 2nd Ed. (1999)). One or more deprotection steps in the synthetic schemes may be required to ultimately afford
compounds of Formula I. The protecting groups depicted in the schemes are used as examples, and may be replaced by other compatible alternative groups. Starting materials used in the following schemes can be purchased or prepared by methods described in the chemical literature, or by adaptations thereof, using methods known by those skilled in the art, The order in which the steps are performed can vary depending on the protecting or functional groups introduced and the reagents and reaction conditions used, but would be apparent to those skilled in the art.
Compounds of Formula I can be prepared as shown in general in Scheme 1. Briefly, in step 1, an alcohol (where the ring substituted by RA, RB, Rc, RD corresponds to ring A of
Formula I) (see, e.g., Intermediate 1) in dioxane is treated with a dichloro heterocycle (e.g., 2- amino-4J6-dichloropyrimidine) in the presence of a base (e.g., Cs2C03), and heated for several hours (e.g. 12-24 h) at reflux. In step 2, a spirocycle of formula B (e.g., (S)-2-benzyl 3-ethyl 2,8- diazaspii [4.5]decane-2,3-dicarboxylate) is added to a solution of compound A in a solvent (e.g., dioxane) in the presense of a base (e.g. Na2CC<3)} and heated to reflux to provide a compound of formula C. In step 3, the amino protecting group (P) (e.g. CBZ or BOC) of a compound of formula C is removed (e.g. with TMSI, transition metal-catalyzed hydro genation, or strong acid depending on the nature of the protecting group). In step 4 , a compound of formula D is obtained by ester hydrolysis (e.g. with LiOH in aqueous THF). In some instances, the sequence of steps 3 and 4 can be reversed.
Figure imgf000051_0001
Step l
P = amino protecting group
(e.g. CBZ or BOC)
Figure imgf000051_0002
eps
Scheme 1 Alcohols (e.g., Intermediate 1) used in Scheme 1 can be prepared as shown in Scheme 2.
Briefly, in step 1, to a solution of base (e.g. potassium f-butoxide) in a solvent (e.g. DMSO) is added 3 -methyl pyrazole and an aryl bromide E (e.g., l,4-dibromo-2-fluoiObenzene), and the mixture is heated for several hours (e.g. 12-24 h) to provide a compound of formula F, In step 2, a compound of formula F is treated with a a Grignard reagent (e.g., -PrMgCl) in a solvent (e.g., THF), then reacted with ethyl trifluoroacetate in a solvent (e.g., THF) to provide a ketone of formula G.
Alternatively, a ketone of formula G can be obtained by treating first a fluoro aromatic compound of formula El with a strong base (e.g., LDA), then trapping the intermediate aryl lithium with trifluoroacetic acid ethyl ester to give a compound of formula Fl (Step l ). In a subsequent step 2a, 3 -methyl pyrazole can be introduced onto a ketone of formula Flvia an
SNAr reaction in the presence of base (e.g., K2C03) under solvent reflux (e.g., toluene). In step 3, a ketone of formula G is converted stereospecifically into a chiral alcohol of formula H via either chiral transfer hydrogenation (e.g., with potassium formate) in the presence of a transition metal catalyst (e.g., pentamethyl cyclopentadienyl iridium (III) chloride dimer) and a chiral ligand (e.g., (lR,2R)-(-)-N-(4-toluene sulfonyl)-l,2-diphenyl ethylene diamine) in a solvent (e.g., acetonitrile), or alternatively with a faorane reagent (e.g. catechol borane) and a chiral catalyst (e.g. (S)-2-methyl-CBS oxazaborolidine) in a solvent (e.g., THF). Alternatively, an alcohol of formula K can be made in a similar fashion starting from a ketone of formula J (step 2c). A ketone of formula J can be prepared in one step (step 2c) by reacting the aryl ester of formula E2 with a nucleophilic silylating agent (e.g., trimethyl(trifluoromethyi)silane) in the presence of a fluoride source (e.g., TBAF) in an inert solvent (e.g., THF).
Figure imgf000052_0001
OR
Figure imgf000052_0002
Scheme 2
Other types of oxygen or nitrogen linker groups (L-groups) can be installed as shown in Scheme 3. Briefly, in step 1, to a spirocyclic compound of B (e.g., (S)-2-benzyl 3-ethyl 2,8- diazaspiro[4.5]decane-2,3-dicarboxylate) in dioxane is added a di-halo heterocycle (e.g., 2- amino-4,6-dichloi pyrimidine) in the presence of a base (e.g., Cs2C03) under solvent reflux (e.g., dioxane) to provide a compound of formula M. In step 2, to a compound of formula M in a solvent (e.g., dioxane) is added an alcohol or an amine of formula O (e.g., Intermediate 7 or 16) in the presence of a base (e.g., Cs C03). After heating at reflux for several hours (e.g., 12-24 h), a compound of formula P is obtained. In step 3, the amino protecting group (P) (e.g., CBZ or BOC) of a compound of formula P is removed (e.g., with TMSI, transition metal-catalyzed hydrogenation, or acid). Then, in step 4, a compound of formula Q is obtained by ester hydrolysis (e.g., with LiOH in aqueous THF). In some instances, the sequence of steps 3 and 4 can be reversed.
Figure imgf000053_0001
Scheme 3
For certain substituents and substitution patterns, palladium-mediated coupling reactions (e.g., Suzuki or Stille reactions) can be used, as shown in Schemes 4a, 4b, and 4c. Briefly, in step 1 , to a compound of formula R in a solvent (e.g., aqueous dioxane) is added a boronic acid or boronate (e.g., phenyl boronic acid) in the presence of a palladium catalyst (e.g., PdCla(dppf)- CH2CI2) and a base (e.g., KHCO3), and the mixture heated to reflux for several hours (e.g., 12- 24) to provide a compound of formula S. In step 3, the amino protecting group (P) (e.g., CBZ or BOC) of a compound of formula S is removed (e.g., with TMSI, transition metal-catalyzed hydrogenation, or acid). Then, in step 4, a compound of formula T is obtained by ester hydrolysis (e.g., with LiOH in aqueous THF). In some instances, the sequence of steps 2 and 3 can be reversed. A similar set of conditions can be used when starting with a compound of formula U or X, to obtain a compound of formula W or AA, respectively (Schemes 4b and 4c).
Figure imgf000054_0001
Scheme 4a
Figure imgf000054_0002
Steps 2 & 3
Scheme 4b
Figure imgf000055_0001
Scheme 4c
Various substitutions of the central 6-membered ring (e.g., the ring containing W, X, and Y) can be accomplished as shown in Scheme 5. Briefly, in step 1, to a solution of a methyl sulfide of formula AB in an inert solvent (e.g., CH2C12) is added an oxidant (e.g., m-CPBA). The solution is stirred at RT for several hours (e.g., 12-24 h) to provide a sulfone of formula AC. In step 2, to a solution of a compound of formula AC in a solvent (e.g., dioxane) is added a spirocyclic compound of formula B (e.g., (S)~2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3- dicarboxylate) in the presence of a base (e.g., CS2CO3), and the mixture is heated for several hours (e.g., 12-24 h) to provide a sulfone of formula AD. In step 3, the ester group is saponified (e.g., with LiOH) in an aqueous or alcoholic solvent (e.g., aqueous THF) to provide an acid of formula AE. In step 4, heating an acid of formula AE in the presence of an alcohol or an amine (e.g., phenol) and a base (e.g., Cs2C03) for several hours (e.g., 16-24 h) in a solvent (e.g., dioxane), followed in step 5 by deprotection of the amine (e.g. with TMSI, transition metal- catalyzed hydrogenation, or acid) provides a compound of formula AF.
Figure imgf000056_0001
Scheme 5
Ester group substituents can be introduced by the general method of Scheme 6. Briefly, in step 1, to a solution of an acid of formula AG in an inert solvent (e.g., CH2C12) is added a coupling reagent (e.g., EDCI and DMAP), followed by an alcohol (e.g., propanol) to provide a compound of formula AH. In step 2, the benzyl groups of the benzyl ester and of the N-CBZ group can be removed with reagents such as TMSI or by transition metal-catalyzed
hydrogenation (e.g., H2 with Pd/C), affording a compound of formula AI. In case the amino protecting group is a BOC, an additional step 3, involving treatment with a strong acid (e.g., TFA), can be used for the final deprotection,
Figure imgf000057_0001
Figure imgf000057_0002
Al
Scheme 6
Ethyl esters can be generally prepared according to Scheme 7, Briefly, deprotection of the amino group in a compound of formula AJ, can be accomplished either with the use of a dealkylating agent (e.g., TMSI) or via transition metal-catalyzed hydrogenation (e.g., H2 with Pd/C) if the protecting group is CBZ, or with a strong acid (e.g., TFA or HCl), if the protecting group is BOC, to provide AK. It will be recognized by those skilled in the art that many other protecting groups can be used alternatively (for example, see Greene, Wuts, Protective Groups in
Figure imgf000057_0003
AJ AK
P = amino protecting group
(e.g. CBZ or BOC)
Scheme 7 Various esters can be made via direct alcohol coupling to the acid, as shown in Scheme 8, or via alkylation of the acid, as shown in Scheme 9. Briefly, an amino acid of formula AL is dissolved in an alcoholic solvent (e.g., n-octanol), optionally in the presence of a co-solvent (e.g., toluene), and heated in the presence of acid (e.g., p-TSA) for several hours (e.g., 12-24 h), optionally in the presence of a water trapping material (e.g., molecular sieve) or apparatus (e.g., Dean-Stark trap) to produce an ester of formula AM. Alternatively, in step 1 , an acid of formula AN is dissolved in a solvent (e.g., DMF) in the presence of a base (e.g., K2CO3) and treated with an alkyl halide (e.g., 2-chloro-ethyl-dimethyl-amine). After heating the solution for several hours (e.g., 12-24 h), an ester of formula AO is obtained. In step 2, removal of the amino protecting group (e.g., with an acid like TFA in an inert solvent such as CH2Cla in case of a BOC protecting group) provides an ester of formula AP. Other compatible deprotection methods app
Figure imgf000058_0001
Step 1
Scheme 8
Figure imgf000059_0001
Figure imgf000059_0002
Step 2 AP
Scheme 9
/-Butyl esters can be made via direct alcohol coupling to the acid, as shown in Scheme 10. Briefly, in step 1, an acid of formula AQ is dissolved in a solvent (e.g., DMF) in the presence of t-butanol, and treated with a coupling agent (e.g., EDCI and DMAP) to provide a compound of formula AR. In step 2, removal of the amino protecting group is achieved as described earlier to afford a compound of formula AS.
Figure imgf000060_0001
AS
Scheme 10
Methods of Use
The compounds of the invention can be used to inhibit the activity of the TPH1 enzyme in a cell by contacting the cell with an inhibiting amount of a compound of the invention. The cell can be part of the tissue of a living organism, or can be in culture, or isolated from a living organism. Additionally, the compounds of the invention can be used to inhibit the activity of the TPH1 enzyme in an animal, individual, or patient, by administering an inhibiting amount of a compound of the invention to the cell, animal, individual, or patient.
Compounds of the invention can also lower peripheral serotonin levels in an animal, individual, or patient, by administering an effective amount of a compound of the invention to the animal, individual, or patient. In some embodiments, the compounds of the invention can lower levels of peripheral serotonin (e.g., 5-HT in the GI tract) selectively over non-peripheral serotonin (e.g., 5-HT in the CNS). In some embodiments, the selectivity is 2-fold or more, 3- fold or more, 5-fold or more, 10-fold or more, 50-fold or more, or 100-fold or more.
As TPH1 inhibitors that can lower peripheral serotonin levels, the compounds of the invention are useful in the treatment and prevention of various diseases associated with abnormal expression or activity of the TPH1 enzyme, or diseases associated with elevated or abnormal peripheral serotonin levels. In some embodiments, the treatment or prevention includes administering to a patient in need thereof a therapeutically effective amount of a TPHl inhibitor of the invention.
Biological assays, some of which are described herein, can be used to determine the inhibitory effect of compounds against TPH (such as TPHl) in vitro and/or in vivo. In vitro biochemical assays for human, mouse, and rat TPHl and human TPH2, PheOH, and TH may be used to measure inhibition of enzyme activity and the selectivity among TPHl, TPH2, PheOH, and TH. In addition, the efficacy of these compounds can be determined, for example, by measuring their effect on intestinal 5-HT levels in rodents after oral administration.
Diseases treatable or preventable by administering a TPHl inhibitor of the invention include bone disease such as, for example, osteoporosis, osteoporosis pseudoglioma syndrome (OPPG), osteopenia, osteomalacia, renal osteodystrophy, Paget's disease, fractures, and bone metastasis, In some embodiments, the disease is osteoporosis, such as primary type 1 (e.g., postmenopausal osteoporosis), primary type 2 (e.g., senile osteoporosis), and secondary (e.g., steroid- or glucocorticoid-induced osteoporosis).
The present invention further includes methods of treating or preventing bone fracture such as, for example, osteoporotic or traumatic fracture, or surgical fractures associated with an orthopedic procedure (e.g., limb lengthening, bunion removal, an increase in bone formation associated with a prosthesis, bone metastasis, or spinal fusion).
Further diseases treatable or preventable by the methods of the invention include cardiovascular diseases such as atherosclerosis and pulmonary hypertension (PH), including idiopathic or familial PH, and also including PH associated with or brought on by other diseases or conditions. In some embodiments, the PH disease is pulmonary arterial hypertension (PAH).
The types of PAH treatable according to the methods of the invention include (1) idiopathic (IPAH), (2) familial (FPAH), and (3) associated (APAH) which is the most common type of PAH, The latter is PAH which is associated with other medical conditions including, for example, (1) collagen vascular disease (or connective tissue disease) which include autoimmune diseases such as scleroderma or lupus; (2) congenital heart and lung disease; (3) portal hypertension (e.g., resulting from liver disease); (4) HIV infection; (5) drugs (e.g., appetite suppressants, cocaine, and amphetamines; (6) other conditions including thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia,
hemoglobinopathies, myeloproliferative disorders,and splenectomy. APAH can also be PAH associated with abnormal narrowing in the pulmonary veins and/or capillaries such as in pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis. Another type of PAH is associatead with persistent pulmonary hypertension of the newborn (PPHN).
Further diseases treatable or preventable by the methods of the invention include metabolic diseases such as diabetes and hyperlipidemia; pulmonary diseases such as chronic obstructive pulmonary disease (COPD), and pulmonary embolism; gastrointestinal diseases such as IBD, colitis, chemotherapy- induced emesis, diarrhea, carcinoid syndrome, celiac disease, Crohn's disease, abdominal pain, dyspepsia, constipation, lactose intolerance, MEN types I and II, Ogilvie's syndrome, pancreatic cholera syndrome, pancreatic insufficiency,
pheochromacytoma, scleroderma, somatization disorder, Zollinger-Ellison Syndrome, or other gastrointestinal inflammatory conditions; liver diseases such as chronic liver disease; cancers such as liver cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, and bone cancer (e.g., osteosarcoma, chrondrosarcoma, Ewings sarcoma, osteoblastoma, osteoid osteoma, osteochondroma, enchond oma, chondromyxoid fibroma, aneurysmal bone cyst, unicameral bone cyst, giant cell tumor, and bone tumors); blood diseases (e.g., myeoloproliferative syndrome, myelodysplasia syndrome, Hodgkin's lymphoma, non-Hodgkin's lymphoma, myeloma, and anemia such as aplastic anemia and anemia assocated with kidney disease; and blood cancers (e.g., leukemias such as acute lymphocytic leukemia (ALL), chronic lymphocytic leukemica (CLL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML)).
The compounds of the invention are also useful in the treatment and prevention of serotonin syndrome.
In some embodiments, the present invention includes methods of lowering plasma cholesterol, lowering plasma triglycerides, lowering plasma glycerol, lowering plasma free fatty acids in a patient by administering to said patient a therapeutically effective amount of a compound of the invention.
The compounds of the invention are also useful in the treatment and prevention of inflammatory disease, such as allergic airway inflammation (e.g., asthma).
As used herein, the term "cell" is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal.
As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" the enzyme with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having the TPH1 enzyme, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the TPH1 enzyme.
As used herein, the term "individual" or "patient," used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
As used herein, the phrase "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
As used herein the term "treating" or "treatment" refers to 1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), or 2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).
As used herein the term "preventing" or "prevention" refers to inhibiting onset or worsening of the disease; for example, in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
Combination Therapy
One or more additional pharmaceutical agents or treatment methods can be used in combination with the compounds of the present invention for treatment or prevention of various diseases, disorders or conditions disclosed herein. The agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially in separate dosage forms.
Example pharmaceutical agents that may be useful in a combination therapy for blood disorders like blood cancers include parathyroid hormone, anti-sclerostin antibodies, kathepsin K inhibitors, and anti-Dickopff 1.
Example pharmaceutical agents that may be useful in a combination therapy for cancer include leuprolide, gosereiin, buserelin, flutamide, nilutamide, ketoconazole, aminoglutethimide, mitoxantrone, estramustine, doxorubicin, etoposide, vinblastine, paclitaxel, carboplatin, and vinorelbine. Therapies that can be combined with TPH inhibition include radiation therapy, high- intensity focused ultrasound, or surgery (e.g., removal of diseased tissues). Other drugs for use in treating cancer include testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, GnRH-analogues, temozolomide, bavituximab, cyclophosphamide, fluorouracil, fulvestrant, gefitinib, trastuzumab, IGF-1 antibodies, lapatinib, methotrexate, olaparib, BSI-201, pazopanib, rapamycin, ribavirin, sorafenib, sunitinib, tamoxifen, docetaxel, vataHnib, bevacizumab, and octreotide.
Example pharmaceutical agents that may be useful in combination therapy for cardiovascular or pulmonary diseases include endothelin receptor antagonists such as ambrisentan, BMS-193884, bosentan, darusentan, SB-234551, sitaxsentan, tezosentan and macitentan. Anticoagulants such as warfarin, acenocoumarol, phenprocoumon, phenindione, heparin, fondaparinux, argatroban, bivaliiudin, lepirudin, and ximelagatran may also be useful in combination therapy. Pharmaceutical agents for combination therapy further include calcium channel blockers like amlodipine, felodipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, lacidipine, lercanidipine, phenylalkylamines, verapamil, gallopamil, diltiazem, and menthol. Prostacyclins like epoprostenol, iloprost and treprostinil may also be combined with the TPH inhibitors of the invention. Further pharmaceutical agents for combination therapy in cardiovascular or pulmonary diseases include PDE5 inhibitors like sildenafil, tadalafil, and vardenafil; diuretics like furosemide, ethacrynic acid, torasemide, bumetanide,
hydrochlorothiazide, spironolactone, mannitol, nitric oxide or nitric oxide releasers, and soluble guanylate cyclase stimulators, such as riociguat. Yet further pharmaceutical agents for combination therapy include APJ receptor agonists (WO 2013/11 11 10); IP receptor agonists (WO 2013/105057; WO 2013/105066; WO 2013/105061; WO 2013/105063; WO 2013/105065; WO 2013/105058); and PDGF receptor inhibitors (WO 2013/030802).
Example pharmaceutical agents that may be useful in combination therapy for metabolic disorders include HSL inhibitors such as those disclosed in International Patent Publications WO2006/074957; WO2005/073199; WO2004/1 1 1031 ; WO2004/1 1 1004; WO2004/035550; WO2003/051841; WO2003/051842; and WO2001/066531.
Example pharmaceutical agents that may be useful in combination therapy for bone disorders and diseases include bisphosphantes such as etidronate, clodronate, tiludronate, pamidronate, neridronate, oipadronate, alendronate, ibandronate, risedronate, cimadronate, zoledronate, and the like. Serotonin receptor modulators, such as 5-HTIB , 5-HT2A, and 5-HT2B agonists or antagonists, may also be useful in combination therapy for bone disease. Other useful agents for combination therapy include selective serotonin reuptake inhibitors (SS I), anti-serotonin antibodies, and beta blockers such as IPS339, ICI1 18,551, butaxamine, metipranolol, nadol, oxprenolol, penbutolol, pindolol, propranolol, timolol, and sotalol, Further useful agents for combination therapy for the treatment of bone disorders, such as osteoporosis, include teriparatide, strontium ranelate, raloxifene, and denosumab,
Administration, Pharmaceutical Formulations, Dosage Forms
The compounds of the invention can be administered to patients (animals and humans) in need of such treatment in appropriate dosages that will provide prophylactic and/or therapeutic efficacy. The dose required for use in the treatment or prevention of any particular disease or disorder will typically vary from patient to patient depending on, for example, particular compound or composition selected, the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors. The appropriate dosage can be determined by the treating physician.
A compound of this invention can be administered orally, subcutaneously, topically, parenteral ly, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Parenteral
administration can involve subcutaneous injections, intravenous or intramuscular injections or infusion techniques. Treatment duration can be as long as deemed necessary by a treating physician. The compositions can be administered one to four or more times per day. A treatment period can terminate when a desired result, for example a particular therapeutic effect, is achieved. Or a treatment period can be continued indefinitely.
In some embodiments, the pharmaceutical compositions can be prepared as solid dosage forms for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules and the like). A tablet can be prepared by compression or molding. Compressed tablets can include one or more binders, lubricants, glidants, inert diluents, preservatives, disintegrants, or dispersing agents, Tablets and other solid dosage forms, such as capsules, pills and granules, can include coatings, such as enteric coatings,
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration can include, for example, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Suspensions can include one or more suspending agents
Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
Compositions and compounds of the present invention can be administered by aerosol which can be administered, for example, by a sonic nebulizer.
Pharmaceutical compositions of this invention suitable for parenteral administration include a compound of the invention together with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions.
Alternatively, the composition can be in the form of a sterile powder which can be reconstituted into a sterile injectable solutions or dispersion just prior to use.
The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner, Those of skill in the art will readily recognize a variety of non-critical parameters which can be changed or modified to yield essentially the same results. The compounds of the Examples were found to be inhibitors of TPH1 as described below. EXAMPLES
The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that a!l proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials.
*H NMR Spectra were acquired on one or more of three instruments: (1) Agilent
Unitylnova 400 MHz spectrometer equipped with a 5 mm Automation Triple Broadband (ATB) probe (the ATB probe was simultaneously tuned to Ή, 19F and 13C); (2) Agilent Unitylnova 500 MHz spectrometer; or (3) Varian Mercury Plus 400 MHz spectrometer. Several NMR probes were used with the 500 MHz NMR spectrometer, including both 3 mm and 5 mm ¾, 19F and !3C probes and a 3 mm X'H19F NMR probe (usually X is tuned to 13C). For typical Ή NMR spectra, the pulse angle was 45 degrees, 8 scans were summed and the spectral width was 16 ppm (-2 ppm to 14 ppm). Typically, a total of about 32768 complex points were collected during the 5.1 second acquisition time, and the recycle delay was set to 1 second. Spectra were collected at 25 °C. Ή NMR Spectra were typically processed with 0.3 Hz line broadening and zero-filling to about 1 1072 points prior to Fourier transformation. Chemical shifts were expressed in ppm relative to tetramethylsilane. The following abbreviations are used herein: br = broad signal, s = singlet, d = doublet, dd = double doublet, ddd = double double doublet, dt = double triplet, t = triplet, td = triple doublet, tt = triple triplet q = quartet, m = multiplet.
Liquid chromatography - mass spectrometry (LCMS) experiments to determine retention times and associated mass ions were performed using one or more of the following Methods A, B, and C:
Method A: Waters BEH C18, 3,0 x 30 mm, 1.7 μιτι, was used at a temperature of 50 °C and at a flow rate of 1.5 mL/min, 2 μΤ injection, mobile phase: (A) water with 0.1% formic acid and 1% acetonitrile, mobile phase (B) MeOH with 0.1% formic acid; retention time given in minutes. Method A details: (1) ran on a Binary Pump G1312B with UV/Vis diode array detector G1315C and Agilent 6130 mass spectrometer in positive and negative ion electrospray mode with UV PDA detection with a gradient of 15-95% (B) in a 2.2 min linear gradient (II) hold for 0.8 min at 95% (B) (III) decrease from 95-15% (B) in a 0.1 min linear gradient (IV) hold for 0.29 min at 15% (B);
Method B: An Agilent Zorbax Bonus RP, 2.1 x 50 mm, 3.5 μιη, was used at a temperature of 50 °C and at a flow rate of 0.8 mL/min, 2 ΐ, injection, mobile phase: (A) water with 0.1% formic acid and 1% acetonitrile, mobile phase (B) MeOH with 0.1% formic acid; retention time given in minutes, Method details: (I) ran on a Binary Pump G1312Bwith UV/Vis diode array detector G1315C and Agilent 6130 mass spectrometer in positive and negative ion electrospray mode with UV-detection at 220 and 254 nm with a gradient of 5-95% (B) in a 2.5 min linear gradient (II) hold for 0.5 min at 95% (B) (III) decrease from 95-5% (B) in a 0.1 min linear gradient (IV) hold for 0.29 min at 5% (B).
Method C: An API 150EX mass spectrometer linked to a Shimadzu LC- 1 OAT LC system with a diode array detector was used. The spectrometer had an electrospray source operating in positive and negative ion mode. LC was carried out using an Agilent ZORBAX XDB 50 x 2.1 mm CI 8 column and a 0.5 mL/minute flow rate. Solvent A: 95% water, 5% acetonitrile containing 0.01% formic acid; Solvent B: acetonitrile. The gradient was shown as below. 0-0.5 min: 2% solvent (B); 0.5-2.5 min: 2% solvent B to 95% solvent (B); 2.5-4.0 min: 95% solvent (B); 4.0-4.2 min: 95% solvent (B) to 2% solvent B; 4.2-6.0 min: 2% solvent (B).
Microwave experiments were carried out using a Biotage Initiator™, which uses a single- mode resonator and dynamic field tuning. Temperatures from 40-250 °C were achieved, and pressures of up to 20 bars were reached.
Preparative HPLC purification was carried out using either a CI 8 -reverse-phase column from Genesis (CI 8) or a C6-phenyl column from Phenomenex (C6 Ph) (100 x 22.5 mm i.d. with 7 micron particle size, UV detection at 230 or 254 nm, flow 5-15mL/min), eluting with gradients from 100-0 to 0-100 % water/acetonitrile or water/MeOH containing 0.1% formic acid. Fractions containing the required product (identified by LCMS analysis) were pooled, the organic fraction removed by evaporation, and the remaining aqueous fraction lyophilised, to give the product. Chiral HPLC was carried out using a Chiralpak AD column, 4.4 mm x 250 mm, particle size 5 micron
Compounds which required column chromatography were purified manually or fully automatically using either a Biotage SP1™ Flash Purification system with Touch Logic
Control™ or a Combifiash Companion® with pre-packed silica gel Isolute® SPE cartridge, Biotage SNAP cartridge or Redisep® Rf cartridge respectively.
Preparation of alcohols and amines
The chiral alcohols drawn below are shown in their absolute configuration (unless otherwise shown). Their enantiopurity (% ee) can be determined via Mosher ester analysis and analyzed as described in the literature (Dale, J, A, & Mosher, H. S. Nuclear Magnetic Resonance Enantiomer Regents, Configurational Correlations Via Nuclear Magnetic Resonance Chemical Shifts Of Diastereomeric Mandelate, O-Methylmandelate, and alpha-Methoxy alpha- Trifluoromethylphenylacetate (MTPA) Esters. J, Am. Chem. Soc. 95, 512-519 (1973)). The chiral alcohols of the invention are preferably enantiomerically enriched, for example, to > 95% ee,
Representative Mosher ester preparation
To a solution of (R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2)2,2- trifluoroethanol (46 mg, 0.20 mmol, Intermediate 3) was added pyridine (138 mg, 1.7 mmol) followed by the addition of either (S or R)-a-methoxy-a-trifluoromethyl-phenyIacetyl chloride (10 mg, 0.40 mmol), The reaction was stirred for 12 h, then the material was purified directly on silica gel chromatography (EtOAc heptane) to provide the "Mosher ester" which was analyzed by lH NMR for enantiomeric purity.
Intermediate 1 : (R)-l-(4-Bromo-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethanoi
Figure imgf000069_0001
Step 1: Potassium /-butoxide (16.3 g, 145 mmol) was dissolved in DMSO (100 mL). To this solution was added 3-methyl pyrazole (10.4 g, 120 mmol) and the reaction was heated at 50 °C for 30 min. l ,4-Dibromo-2-fluorobenzene (31 g, 120 mmol) was then added and the reaction stirred at 50 °C for 16 h. The reaction was cooled to RT and extracted with water and EtOAc, washed with brine, dried over Na2S04, and then filtered and concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtO Ac/heptane) provided 1 -(2,5- dibromophenyl)-3-methyl-lH-pyrazole.
Step 2: l -(2,5-dibromophenyl)-3-methyl-lH-pyrazole (23.0 g, 73 mmol) from Step 1 was dissolved in 200 mL of THF and cooled to 0 °C. /-Propyl magnesium chloride (2.0 M in THF, 40 mL) was added dropwise and the reaction was stirred for 45 min, then ethyl trifluoroacetate (10.5 mL) was added. The reaction was stirred for 30 min at 0 °C, then 10% HC1 is added dropwise (400 mL), The reaction was extracted with water and EtOAc, washed with brine, dried over Na2S04, filtered, and then concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtOAc/heptane) provided l-(4-bromo-2-(3-methyl-lH-pyrazol-l-yl)phenyl)- 2,2,2 -trifluoroethanone.
Step 3: METHOD A: Pentamethylcyclopentadienyl iridium (III) chloride dimer (CAS# 12354- 84-6) (10,4 mg) and (lR,2R)-(-)-N-(4-toluene sulfonyl)-l ,2-diphenyl ethylene diamine (CAS# 144222-34-4) (9.2 mg) were combined in water ( 120 mL), then heated to 50 °C for 5 h to provide the "Iridium complex." l-[4-Bromo-2-(3 -methyl- 1 H-pyiazol- 1 -yl)phenyl] -2,2,2- trifluoroethanone (16 g, 48 mmol) was dissolved in acetonitrile (120 mL) to which the Iridium complex and potassium formate (3.1 g, 3,7 mmol) were added. The reaction mixture was heated to 50 °C for 8 h, The reaction mixture was then cooled to RT, partitioned between water and EtOAc, and extracted. The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. Recrystallization from hot heptane (200 mL) provided the title compound.
METHOD B: Alternatively, the trifiuoromethyl (or other prochiral) ketones of formula G or J (scheme 2) were asymmetrically reduced as follows (see for example: Corey, E. J. & Link, J. O, A General, Catalytic, and Enantioselective Synthesis of Alpha-amino Acids, J, Am. Chem. Soc. 114, 1906-1908 (1992)): Catechol borane (95 mL, 1 M in THF) and (S)-2-methyl-CBS oxazaborolidine (2.6 g, 9.6 mmol) were mixed in a jacketed glass reactor. The mixture was stirred at RT for 20 min, then the jacket was cooled to -78 °C. At a reaction temperature of -65 °C, l-[4-biOino-2-(3-methyl-lH-pyrazol-l-yl)phenyl]-2)2,2-trifluoiOethanone (16 g, 48 mmol) in THF (150 mL) was added dropwise over 2 h. The reaction was then warmed to -36 °C and held at this temperature for 22 h. Then the reaction was quenched with 3 N NaOH (100 mL) while maintaining a reaction temperature of <-25 °C. The reaction was then warmed to 0 °C and H202 (30%, 100 mL) was added over 30 min, then warmed to RT for 4 h. The reaction mixture was quenched with 1 N NaOH, extracted with ether, washed with brine, dried over Na2S04, and concentrated in vacuo. Purification on normal phase silica gel chromatography (EtO Ac/heptane) provided the product as a viscous oil.
Intermediate 2: (R)-l-(5-Bromo-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethanol
Figure imgf000071_0001
Step 1: Diisopropylamine (4.40 mL, 31.4 mmol) was dissolved in THF (28 mL) and cooled to
-40 °C, Then n-butyllithium (12.6 mL, 2.5 M in hexanes, 31.4 mmol) was added dropwise, and the reaction was stirred at -40 °C for 1 h, then cooled to -78 °C, A solution of l-bromo-4-fluoiO- benzene (5 g, 28.6 mmol) in THF (6.0 mL) was added, and the reaction was stirred at -78 °C for 1 h. Trifluoroacetic acid ethyl ester (3.73 mL, 31.4 mmol) in THF (6.0 mL) was then added, and the reaction was slowly warmed to 0 °C over an hour. The reaction was quenched with NH4C1
(aq, sat), and extracted with EtOAc, washed with brine, and dried over a2S0 , filtered, and concentrated in vacuo. Purification by normal phase silica gel column chromatography
(EtO Ac/heptane) provided 1 -(5-biOmo-2-fluorophenyl)-2;2,2-trifluoroethanone.
Step 2: l -(5-bromo-2-fluoi phenyl)-2,2,2-trifluoroethanone (2.20 g, 8.12 mmol) from Step 1, K2CO3 (1.68 g, 12.2 mmol), and 3-methyl-lH-pyrazole (1.33 g, 1 .2 mmol) were stirred in toluene (10 mL). The reaction was then heated to 110 °C for 16 h. The reaction was cooled, and water and EtOAc were added. The toluene-EtOAc layer is removed in vacuo, and then the reaction is extracted with water and EtOAc, washed with brine, and dried over Na S04, filtered, and concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtO Ac/heptane) provided l-[5-biOmo-2-(3-methyl-pyrazol-l-yl)-phenyl]-2)2,2-trifluoro- ethanone.
Step 3: The title compound was prepared using the Iridium complex-catalyzed hydrogenation as described for Intermediate 1, (R)-l-(4-bromo-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethanol.
Intermediate 3: (R)-l-(4-chIoro-2-(3-methyl-lH-pyrazoI-l-yl)p enyl)-2,2,2-trifluoroethanol
Figure imgf000072_0001
Step 1: Potassium /-butoxide (3.9 g, 0.33 mmol) was dissolved in DMSO (25 mL). To this solution was added 3 -methyl pyrazole (2.7 g, 0.33 mmol) and the reaction was heated at 50 °C for 30 min. l-Bromo-4-chloro-2-fluorobenzene (4.6 g, 0.22 mmol) was then added and the reaction was stirred at 50 °C for 16 h. The reaction was cooled to RT and extracted with water and EtOAc, washed with brine, and dried over Na2S04) filtered and concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtO Ac/heptane) provided l-(2- bromo-5-chlorophenyl)-3-methyl-lH-pyrazole and l-(2-bromo-5-chloroplienyl)-5-methyl-lH- pyrazole as a 4: 1 mixture that was used in the next step directly,
Step 2: The mixture from Step 1 (8 g, 0.39 mmol) was dissolved in 160 mL of THF and cooled to 0 °C. /-Propyl magnesium chloride (2.0 M in THF, 23 mL) was added dropwise and the reaction stirred for 45 min, then ethyl trifluoroacetate (6 mL) was added. The reaction was stirred for 30 min at 0 °C, then 10% HC1 was added dropwise (40 mL). The reaction was extracted with water and EtOAc, washed with brine, and dried over Na2S04, filtered, and concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtOAc/heptane) provided l -(4- chloiO-2-(3-methyi-lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoroethanone as a white solid.
Step 3: The title compound was prepared using the Iridium complex-catalyzed hydro genation, as described for intermediate 1 (R)-l-(4-bromo-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethanol.
Intermediate 4: (R)-l-(5-chIoro-2-(2,2 -trifluoro-l-hydroxyethyl)phenyl)pyrrolidin-2-one
Figure imgf000073_0001
To a solution of (R)- 1 -(4)-2,2,2-trifluoroethanol (300 mg, 1.04 mmol) in toluene (7 mL) was added pyrroiidin-2-one (89 mg, 1.04 mmol), (l S,2S)-Ni,N2-dimethylcyclohexane-l ,2-diamine (74 mg, 0.52 mmol), Cul (50 mg, 0.26 mmol) and K2CO3 (360 mg, 2,6 mmol). The reaction was heated in a sealed tube to 130 °C for 12 h and then cooled to RT, The solids were filtered and the product was purified by normal phase silica gel chromatography (EtOAc:petroieum ether) to to provide the title compound as a white solid.
Intermediate s: (R)-2,2,2-TrifluoiO-l- -methyl-lH-benzo[d]imidazol-4-yI)ethanol
Figure imgf000073_0002
Step 1: 4-Bromo-2-methyl-lH-benzimidazole (500 mg, 2.37 mmol) was dissolved in THF (8 mL) and cooled to -78 °C. /?-Butyllithium (2,3 mL, 2.5 M in hexanes, 5.7 mmol) was added dropwise and the reaction was stirred at -78 °C for 30 min. Trifliioroacetic acid ethyl ester (339 //L, 2,8 mmol) was added and the reaction was stirred at 0 °C for 1 h. The reaction was quenched with HCl (2 N, 4 mL), then extracted with water and EtOAc, washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. Purification by normal phase silica gel column chromatography (CH2Ci2/MeOH/NH40H) provided 2,2,2-trifluoro- 1 -(2-methyl- 1 H- benzoimidazol-4-yi)-ethanone. Step 2: The title compound was prepared using the iridium complex-catalyzed hydrogenation, as described for Intermediate 1 (R)-l-(4-bromo-2-(3-methyl-lH-pyrazol-l-yl)phenyi)-2,2,2~ trifluoroethanol.
Intermediate 6: l-(4-Chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)ethanol
Figure imgf000074_0001
Step 1: l-(2-bromo-5-chloiOphenyl)-3-methyl-lH-pyrazole/l-(2-bi mo-5-chloiOphenyl)-5- methyl-lH-pyrazole mixture (Intermediate 3, step 1) (1.00 g, 3.68 mmol) was dissolved in THF (6 mL) and cooled to 0 °C. /-Propyl magnesium chloride (2.76 mL, 2.0 M in THF, 5.52 mmol) was added dropwise and allowed to warm to RT over 30 min. The reaction was then cooled to -15 °C. Acetyl chloride (481 //L, 5.5 mmol) was added and the reaction was warmed to RT for 3 h. The reaction was quenched with HC1 (2 N, 4 mL), then extracted with water and EtOAc, washed with brine, and dried over N 2S04, filtered, and concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtO Ac/heptane) provided l-[4-chloro-2-(3- methyl-pyrazol- 1 -yl) -phenyl] -ethanone.
Step 2: l-[4-Chloro-2-(3-methyl-pyrazol-l-yl)-phenyl]-ethanone (400 mg, 1.70 mmol) from Step 1 was dissolved in MeOH (10 mL) and cooled to 0 °C. NaBH4 (129 mg, 3.41 mmol) was added portionwise, then the reaction was warmed to RT, stirred for 30 min, then quenched with acetone. The MeOH was removed in vacuo then the residue was partitioned between water and EtOAc and extracted several times. The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. Purification by normal phase silica gel column chromatography (CH2Cl2/MeOH/NH4OH) provided the title compound.
Intermediate 7: l-(2,6-dibromophenyl)ethanol
Figure imgf000075_0001
To a solution of l -(2)6-dibromophenyl)-2)2,2-trifinoiOethanone (CAS# 1208078-23-2) (3 g, 9 mmol) in EtOH (50 mL) was added NaBH4 (340 mg, 9 mmol) at 5 °C. The reaction was warmed to RT for 1 h, then extracted with EtOAc NaHC03, brine, and dried over Na2S04 filtered and concentrated in vacuo to provide l-(2,6-dibiOmophenyl)-2,2,2-trifluoroethanol as a light yellow oil.
Intermediate 8: l-(2,5-dibroinophenyl)ethanol
Figure imgf000075_0002
This compound was made as described above for Intermediate 7, l-(2,6-dibromophenyl)-2J252- trifluoroethanoi, starting with l-(2,5-dibromophenyi)-2,2,2-trifluoroethanone to provide a light yellow oil. Intermediate 9: (4-Chloro-2-(3-methy -lH-pyrazoI-l-yl)phenyl)methanol
Figure imgf000075_0003
Step 1: l-(2-biOmo-5-chlorophenyl)-3-methyl-lH-pyrazole/l-(2-bi mo-5-chlorophenyl)-5- methyl-lH-pyrazole mixture (Intermediate 3, step 1) (1 ,00 g, 3.68 mmol) was dissolved in THF (6 mL) then cooled to 0 °C, /-Propyl magnesium chloride (2,76 mL, 2.0 M in THF, 5.52 mmol) was added dropwise and the reaction was warmed to RT for 30 min. The reaction was then cooled to -15 °C and paraformaldehyde (166 mg, 5.5 mmol) was added. The reaction mixture was allowed to warm to RT and stirred for 1 h. DMF (500 mL) was added and the reaction was stirred for an additional 1 h. The reaction was quenched with HC1 (2 N, 4 mL), diluted with water, extracted with EtOAc, washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtOAc/heptane) provided 4-chloro-2-(3-methyl-pyrazoI-l -yl)-benzaldehyde. Step 2: 4-Chloi -2-(3-methyl-pyrazol-l-yl)-benzaldehyde (446 mg, 2,03 mmol) from Step 1 was dissolved in MeOH (14 mL) and cooled to 0 °C. NaB¾ (175 mg, 4.61 mmol) ) was added portionwise. The reaction mixture was allowed to warm to RT, and after 90 min was quenched with acetone. The MeOH was removed in vacuo. The residue was partitioned between water and EtOAc and then extracted. The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtO Ac/heptane) provided the title compound,
Using the procedure described for Intermediate 3, (R)-l-(4-chloro-2-(3-methyl-lH- pyrazol-l-yljphenylj^^^-trifluoroethanol, the following alcohols (Intermediates 10-15) shown in the Table below were prepared starting with the appropriately substituted l-bromo-2- fluorobenzene,
Figure imgf000076_0001
Figure imgf000077_0001
Intermediate 16: (2-Phenoxy-6-(piperidiii-l-yl)phenyl)methanamine
Figure imgf000077_0002
Step 1: To a solution of phenol (415 mg, 4.5 mmol) in 60 mL of DMF was added NaH (60%, 6.0 mmol) at 0 °C, The reaction was stirred for 1 h, then 2-fluoro-6-(piperidin-l-yi)benzonitrile (CAS# 646989-68-6) (612 mg, 3.0 mmol) was added and the reaction stirred for 48 h at RT. The reaction mixtme was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04) then concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtO Ac/heptane) provided 2- phenoxy-6-(piperidin-l-yl)benzomtnle as an off-white solid.
Step 2: To 2-phenoxy-6-(piperidin-l-yl)benzonitrile (250 mg, 0.9 mmol) from Step 1 in 20 mL of MeOH was added Raney Nickel (5%) and NH4OH (2 mL). The reaction was stirred under 1 atm of ¾ at RT for 2 h. The solid was filtered away and the filtrate was concentrated in vacuo to provide the title compound as a viscous oil.
Intermediate 17: (R)-l-(4-ChIoro-2-( -methoxyethoxy)phenyl)-2,2,2-trifluoroethanol
Figure imgf000078_0001
Step 1: l-Bromo-4-chloro-2-(2-methoxy-ethoxy)-benzene (CAS# 1245563-20-5) (5.00 g, 18.8 mmol) was dissolved in THF (30 mL) and cooled to 0 °C. /-Propylmagnesium bromide (11.3 mL, 2.0 M in THF, 22.6 mmol) was added dropwise, and the reaction was stirred at 10 °C for 30 min, then warmed to RT for 16 h. The reaction was then cooled to -15 °C and trifluoroacetic acid ethyl ester (3.37 mL, 28.2 mmol) was added. The reaction was stirred at 10 °C for 1 h. The reaction was quenched with HC1 (2 N, 38 mL) at 0 °C. The reaction mixture was diluted with water and extracted with EtO Ac. The combined organic layers were washed with brine, dried over Na2S04} then concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtO Ac/heptane) provided l-(4-chloro-2-(2-methoxyethoxy)phenyi)-2,2,2~ trifluoroethanone.
Step 2: The title compound was prepared using the Iridium complex-catalyzed hydrogeneation as described for Intermediate 1 (R)-l -(4-bromo-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethanol.
Intermediate 18: (R)-l-(5-cIiloiO-[l,l,-biphcnyl]-2-yl)-2,2,2-trifluoroethanol
Figure imgf000079_0001
To a solution of (R)-l-(2-biOmo-4-chloiOphenyl)-2,2,2-trifluoroethanol (300 mg, 1.1 mmol) in dioxane (12 mL) was added phenyl boronic acid (185 mg, 1.5 mmol), Pd2(dppf)CI2 (35 mg, 0.07 mmol) and Na2C03(3 mL, 2.0 M, aq). The reaction was heated to 90 °C for 2 h, then cooled to RT, and concentrated in vacuo. The residue was taken up in CH2CI2, washed with brine, and extracted with CLbCh, The combined organic layers were dried over Na2S0 . Purification by normal phase silica gel column (EtOAc/hexanes) to provide a white solid.
Intermediate 19: (R)-l-(4-chloro-2-(5-chlorothiophen-2-yI)phenyI)-2,2,2-trifluoroethanoi
Figure imgf000079_0002
This compound was made in the same way as described for Intermediate 18 (R)-l-(5-chloro- [l, -biphenyl]-2-yl)-2,2,2-trifiuoiOethanol to provide a white solid,
Intermediate 20: (R)-2,2,2-trifluoro-l-(6-methyl-2-(3-methyl-lH-pyrazol-l-yl)pyri(lin-3- yl)ethanol
Figure imgf000079_0003
Step 1: To the solution of 2-chloro-6-methylnicotinic acid (5 g, 29.1 mmol) in CH2C12 (40 mL) was added oxalyl dichloride (8.1 g, 63.8 mmol) at 0 °C and the reaction mixture was stirred for 2 h. The mixture was concentrated and 40 mL of methanol was then added at 0 °C and the reaction mixture was stirred at RT for 12 h. The mixture was then concentrated in vacuo and extracted with EtOAc. The combined organic layers were washed with brine, dried ove a2S04, filtered, and concentrated in vacuo to provide methyl 2-chloro-6-methylnicotinate that is used without further purification as a light yellow solid.
Step 2: To a solution of 3 -methyl- lH-pyrazole (1.1 g, 13.4 mmol) in DMF (5 ml) was added sodium hydride (1.0 g, 60% in oil) at 0 °C. The reaction mixture was stirred for ί h at 0 °C and then . A solution of methyl 2-chloro-6-methylnicotinate (4.3 g, 23.16 mmol) in DMF (5 mL) was added dropwise to the reaction mixture at 0 °C. After addition, the mixture was heated to 80 °C and stirred for 12 h. After this time, the mixture was poured into ice- ater and extracted and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo and then purified by normal phase silica gel column (EtOAc/hepate) to provide methyl 6-methyl-2-(3-methyl-lH~pyrazol-l-yl)nicotinate as a brown semi-solid.
Step 3: To a solution of methyl 6-methyl-2-(3-methyl-lH-pyrazol-l-yl)nicotinate (3.7 g, 16 mmol) and trimethyl(trifiuoromethyl)silane ( 1.4 g, 80.2 mmol) in toluene (60 ml), was added dropwise at -78°C and then the solution of tetrabutyl ammonium fluoride (1.6 mL,l .0 M in THF) was added dropwise to the reaction mixture at -78 °C. After addition, the mixture was warmed slowly up to RT and stirred for 12 h. The reaction mixture was concentrated and the resulting residue was dissolved in methanol (30 mL). 6 N HC1 (30 mL) was added to the reaction mixture and the resulting mixture was stirred for 2 h. The reaction mixture was concentrated, adjusted to pH 6 with sat.NaHC03 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo and purified by normal phase silica gel column (EtOAc hepate) to provide 2}2,2-trifluoro-l-(6-methyl-2-(3-methyl-lH- pyrazoi-l-yl)pyridin-3-yl)ethanone as a brown semi-solid.
Step 4: A solution of (S)-(-)-2-Butyl-CBS-oxazaborolidine solution (3,0 ml 1.0 M in toluene) and catecholborane (30 ml 1.0 M in THF) was stirred at RT for 30 min. The mixture was then cooled to -70 °C and 2,2J2-trifluoiO-l-(6-methyl-2-(3-methyl-i r-I-pyrazol-l -yl)pyridin-3- yl)ethanone (1 g, 2.9 mmol) in THF (16 mL) was added dropwise. After addition, the reaction mixture was warmed up to -32 °C and stirred for 12 h. After this time, 3N NaOH (18 mL) was added followed by H202 (18 mL) and the temperature of the reaction mixture was increased to RT for 30 min and then extracted with ethyl. The combined organic layers were washed with brine, dried over Na2SC , filtered, and concentrated in vacuo and purified by normal phase silica gel column (EtOAc hepate) to provide the title compound as a yellow solid. Intermediate 38: (R)-l-(5-bromo-[l,r-biphenyl]-2-yl)-2,2,2-trifluoroethanol
Figure imgf000081_0001
Step 1: A solution of 2,4-dibromo-benzoic acid, (2,3 g, 18.8 mmol), phenyl boronic acid (5 g, 17.9 mmol), Pd2(dba)3 (818 mg, 8,9 mmol) and Li OH (1.65 g, 39.3 mmol) in a 1: 1 mixture of NMP/water (100 mL) was heated to 70 °C for 2 d. After this time, the reaction mixture was cooled to RT, and the reaction mixture was adjusted to pH = 4-5 with 3 N HC1. The mixture was then extracted with ethyl acetate and the combined organic layers were washed with brine, dried over Na2S0 , filtered, and concentrated in vacuo and purified by normal phase silica gel column (EtOAc/PE 10:1 to 1 : 1) to afford 5-bromo-[l,r-biphenyl]-2-carboxylic acid as a colorless oil. Step 2: To a solution of 5-bi mo-[l, -biphenyl]-2-carboxylic acid (5 g, 18.2 mmol) in MeOH (30 mL) was added SOCl2 (10 mL) dropwise. The reaction mixture was heated to 70 °C for 2 h, then cooled to RT. The mixture was concentrated, adjusted to pH= 7-8 with saturated aqueous NaHC03 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SC>4, filtered, and concentrated in vacuo and purified by normal phase silica gel column (EtOAc/PE 50: 1) to afford afford methyl 5-bromo-[l , -biphenyl]-2-carboxylate as a colorless oil.
Step 3: A solution of methyl 5-bromo-[l ,l'-biphenyl]-2-carboxylate (2,2 g, 6.9 mmol) in THF (50 mL) was cooled to 0 °C. LiAlI¾ (380 mg, 10 mmol) was added slowly. The reaction mixture was stirred at RT for 2 h, after which water (1 mL) was added slowly to quench the reaction. The solid was removed by filtration and the filtrate was concentrated in vacuo to provide (5-bromo- [l,r-biphenyl3-2-yl)methanol as a white solid that was used directly without further purification. Step 4: To a solution of (5-bromo-[l,l'-biphenyl]--2-yl)methanol (2.0 g, 8.4 mmol) in CH2CI2 (30 mL) was added Dess-Martin Periodinane (4.3 g, 10 mmol). The reaction mixture was stirred at RT for 2 h and then the solids were filtered and the resultant filtrate was concentrated in vacuo. Purification by normal phase silica gel column (EtOAc:PE = 1 :50) afforded 5-bromo-[l, - biphenyl]-2-carbaldehyde as a colorless oil.
Step 5: To a solution of 5-bromo-[l,r-biphenyl]-2-carbaldehyde (1.9 g, 7.3 mmol) and was added TMSCF3 (1.2g, 8.7 mmol) in THF (20 mL) and cooled to 0 °C. To this solution was added TBAF (1.46 mL, 1M in THF) and the reaction mixture was warmed to RT for 3 h. After this time, the mixture was treated with 3 N HC1 (5 mL) and stirred for 12 h. Then the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2S0 , filtered, concentrated in vacuo and purified by normal phase silica gel column (EtOAc:PE = 1 : 10) to afford l-(5-bromo-[l, -biphenyl]-2-yl)- 2,2,2-trifluoroethanol as a colorless oil.
Step 6: To a solution of l-(5-biOmo-[l,l'-biphenyl]-2-yl)-2,2,2-trifluoroethano (1.8 g, 5.5 mmol) in CH2CI2 (30 mL) was added Dess-Martin Periodinane (3g, 7.1 mmol). The reaction mixture was stirred at RT for 2 h and then the solids were filtered. The resultant filtrate was concentrated in vacuo. Purification by normal phase silica gel column (EtOAc:PE = 1 :50) afforded l-(5- bromo-[l , 1 '-biphenyl]-2-yl)-2,2,2-trifluoroethanone as a colorless oil.
Step 7: l-(5-Bromo-[l,l'-biphenyl]-2-yl)-2J2,2-trifluoiOethanone (1.3 g, 3.9 mmol) in CH3CN (10 mL) was reduced to the chiral alcohol using the chiral iridium catalyst (METHOD A) at RT. The reaction mixture was then charged with potassium formate (725 mg, 8.6 mmol) and the mixture was stirred at 40 °C for 12 h, Then the reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2S(¾, filtered, concentrated in vacuo and purified by normal phase silica gel column (EtOAc:PE = 1:10) to afford the title compound as a colorless oil. Using the procedure described for Intermediate 3, (R)-l-(4-chloro-2-(3-methyl-lH- pyrazol-l-yl)phenyl)-2,2,2-ttifluoiOethanol, the following alcohols (Intermediates 39-42) shown in the Table below were prepared starting with the appropriately substituted pyrazole.
Figure imgf000083_0001
Intermediate 43: (R)-l-(2-bromo-4-chlorophenyl)-2,2,2-ti ifIuoroethanol
Figure imgf000084_0001
A solution of dichloro(pentamethylcyclopentadienyl)hidram (III) dimer ([Cp^IrChJs, 14 mg, 0.02 mmol) and (ii?,2i?)-(-)-(4-toluenesulfonyl)-l,2-diphenylethylenediamine (14 mg, 0.04 mmoi) in water (7 mL) was prepared at RT. The resulting mixture was heated to 40 °C for 3 h to provide a homogeneous orange solution. To this active catalyst solution at 40 °C was added potassium formate (143 mg, 171 mmol), and a solution of l-(2-bromo-4-chloiOpheny])-2,2,2- trifluoroethanone (CAS# 1033805-23-0, 98 mg, 0.34 mmol) in CH3CN (70 mL). The reaction mixture was then stirred at 40 °C for 2 h and then cooled to RT and the layers were separated. The aqueous layer was extracted with MTBE and the combined organic layers were dried over Na2S0 , filtered, and concentrated in vacuo to provide the title compound that was used without further purification.
The following alcohols and amines in the table below are useful in preparing compounds of the invention. They are either commercially available or can be prepared by known synthetic procedures. CAS registry numbers are provided for each,
Figure imgf000084_0002
Figure imgf000085_0001
Preparation of boronic acids and esters
The boronic acids and esters used in biaryl couplings are either commercially available or can be readily synthesized from the corresponding bromide using routine synthetic methods. The following Intermediate 34 is a representative example. Intermediate 34: 6-(4,4,5)5-Tetramethyl-l,3j2-dioxaborolan-2-yl)-3,4-dihydroquinolin- 2(lH)-one
Figure imgf000086_0001
To a solution of 6-bromo-3)4-dihydroquinoIin-2(lH)-one (200 mg, 0.89 mmol) in 5 n L of acetonitrile was added pinacoldiboron (300 mg, 1.2 mmol), Pd(dppf)2Cl (30 mg, 0.09mmol), KOAc (250 mg, 2.1 mmol) and triethyl amine (ImL). The reaction was heated to 87 °C for 24 h, then cooled to T, The solids were filtered away, and the solvent was removed in vacuo, then extracted with EtOAc, water, brine and dried over Na2S04, The solvent was removed in vacuo to provide an off-white solid which was used without further purification.
Spirocyclic amino esters preparation
Intermediate 35: (S)-2-BenzyI 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate
Figure imgf000086_0002
Step 1: (3S)-8-Tert-butyl 3-ethyl 2,8-diazaspiro[4.5]decane-3,8-dicarboxylate [Example 24 in US Pat. Pub. No. 2012/0101280] (50 g, 160 mmol) in CH2C12 (500 mL), and Et3N (51.7 g, 512 mmol) was cooled to 0 °C. Benzyl chloroformate (34.1 g, 205 mmol) was added dropwise and the mixture was stirred at 0 °C for 3 h. The reaction mixture was washed with water, extracted with CH2Cl2, dried over Na2S04, and concentrated in vacuo to provide (S)-2-benzyl 8-tert-butyl 3-ethyl 2,8-diazaspii [4,5]decane-2,3,8-tricarboxylate as a light yellow oil which was used directly without further purification.
Step 2: To a solution of (S)-2-benzyl 8-tert-butyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3,8- tiicarboxylate (79 g, 160 mmol, Step 1) in CH2C12 (400 mL) was added TFA (182 g, 1600 mmol) dropwise at RT. The reaction mixture was stirred for 3 h then concentrated in vacuo. The residue was quenched with saturated NaHC03 and solid NaHC03 was added until no further gas evolution was noted. The mixture was extracted with EtOAc and the combined organic layers were concentrated in vacuo. Purification by normal phase silica gel column chromatography (CH2Cb/MeOH NH4OH) provided the title compound as a light yellow solid. Intermediate 36: (S)-2-Tert-butyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate
Figure imgf000087_0001
Step I : (S)-2-Benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (2.4 g, 6.9 mmol) in HCl/dioxane (50 mL, 3.3 N) was stirred for 2 h at RT. The solvent was then removed in vacuo to provide (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate hydrochloride which was used directly without further purification.
Step 2: To a solution of (S)-2-benzyl 3-ethyl 2,8-diazaspiiO[4.5]decane-2,3-dicarboxylate hydrochloride and BOC2O (1.5 g, 6.9 mmol) in EtOH (50 mL) was added Pd/C (10%, 2.4 g) and HOAc (cat.). The mixture was degassed and blanked under H2 then stirred at 45 °C at 50 psi of ¾ for 12 h. The solid was filtered away and the filtrate concentrated in vacuo to provide the title compound as a viscous solid,
Intermediate 37: Methyl 3,9-diazaspiro[5.5]undccane-2-carboxylate
Figure imgf000087_0002
To a solution of 3,9-diazaspiro[5.5]undecane-2-carboxylic acid, 3-[(4-methoxyphenyl)methyl]-9- (phenylmethyl)-methyl ester [CAS# 1314388-32-3] (50 mg, 0.12 mmol) i MeOH (2 mL) and water (2 mL) was added a catalytic amount of TFA. The mixture was hydrogenated using a H- cube apparatus under 80 °C / 80 bar 2 cycles. The reaction mixture was cooled to RT then concentrated in vacuo to provide the title compound as a white solid which is used directly.
General synthetic methods Methods for removal of N-Carbobenzyloxy (N-CBZ) protecting group
Method A - Hydrogenation over Pd/C: To a solution of N-CBZ protected compound (1 eq.) in EtOAc was added HO Ac (100 μΐ,) and 5% (w/w) Pd/C (5 mol%). The reaction mixture was degassed, blanketed under H2 (balloon) 3 times, then stirred at RT for 2 h. The reaction was then filtered through a pad of celite that was rinsed with 1 :9 MeOH:EtOAc. The filtrate was concentrated in vacuo. The product was purified by column chromatography using an Isco Gold reversed phase silica cartridge (H20:HOAc: 99: 1 to MeOH:AcOH 99: 1).
Method B - DeaJkylation with TMSI: To a solution of N-CBZ protected compound (1 eq.) in CH3CN was added a solution of TMSI (2.2 eq.) in CH3CN (0.2 M). The reaction mixture was stirred at RT for 2 h then quenched with 1 N HQ to pH 1. The product was purified by column chromatography using an Isco Gold reversed phase silica cartridge (H20:HOAc: 99: 1 to
MeOH:AcOH 99: 1).
General ester hydrolysis with lithium hydroxide: To a solution of an ethyl ester compound (1 eq) in THF (0.18 M) and water (1.4 M) was added L1OH-H2O (10 eq), The mixture was stirred at RT for 1 h. Water was added and the pH was adjusted to 6.5 with 1 N HC1. THF was removed in vacuo, then the solid was precipitated, washed with water, and dried in vacuo to yield the corresponding carboxylic acid. The compounds of the examples were isolated either in the neutral zwitterionic form or as a TFA or HC1 salt.
Example lu: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3-(3-methyl-lH-pyrazol-l-yl)-[l,l'- biphenyl]-4-yl)ethoxy)pyrimi in-4-yl)-2,8-diazaspiiO[4.5]decaiie-3-carboxyIic acid
Figure imgf000088_0001
Step 1: To a solution of (R)-l-(4-bromo-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2J2,2- trifluoroethanol (160 mg, 0.2 mmol, Intermediate 1) in dioxane (2 mL) was added 2-amino-4,6- dichloropyrimidine (100 mg, 0.16 mmol) and Cs2C0 (48 ,g, 0.16 mmol). The reaction was heated to 80 °C for 16 h, cooled to RT, and filtered. The solvent was removed in vacuo and the residue was dissolved in a mixture of CH2CI2 and heptane, concentrated to half the volume, filtered, and concentrated again in vacuo. Purification via normal phase silica gel
chromatography (CH2Cb/Heptane) provided 4-[(lR)-l-[4-bromo-2-(3-methylpyrazol-l- yl)phenyl]-2,2,2-trifluoro-ethoxy]-6-chloiO-pyrimidin-2-amine as an off-white solid. Step 2 To a solution of 4-[(lR)-l -[4-bromo-2-(3-methylpyrazol-l-yl)phenyl]-2,2,2-trifluoiO- ethoxy]-6-chloro-pyrimidin-2-amine (125 mg, 0,3 mmol, Step 1) in dioxane (3 mL) was added (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (95 mg, 0.3 mmol) and Na2C03 (182 mg, 0.35 mmol). The reaction was heated to 90 °C for 130 h, then cooled to RT, filtered, and concentrated in vacuo, Purification by normal phase silica gel column
(EtO Ac/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)- 1 -(4-bromo-2-(3-methyl- 1H- pyrazol-l-yl)phenyl)-2,2,2-trifluoraethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3- dicarboxylate as a white solid.
Step 3: To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l-(4-bromo-2-(3-methyl-lH- pyrazol-l-yl)phenyl)-2,2,2-trifluoi ethoxy)pyrimidin-4-yl)--2,8-diazaspiiO[4,5]decane-2,3- dicarboxylate (300 mg, 0.4 mmol, Step 2) in ethanol (2 mL) and water (0.5 mL) was added phenylboronic acid (143 mg, 0.8 mmol), PdCl2(PPh3)2 (41 mg, 0.058 mmol), and Cs2C03 (390 mg, 1 ,2 mmol). The reaction was heated to 60 °C for 16 h, then cooled to RT, filtered through celite and concentrated in vacuo. Purification by normal phase silica gel column
(EtO Ac/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoiO-l -(3-(3- methyl-lH-pyrazol-l-yl)-[ljr-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 2,3-dicarboxylate as a white solid.
Step 4: A solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2}2-trifluoro-l-(3-(3-methyl-lH- pyrazoI-l-yl)-[l,r-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2}8-diazaspii [4.5]decane-2,3- dicarboxylate (240 mg, 0,4 mmol, Step 3) in EtOAc (5 mL) was hyrogenated using an H-Cube apparatus and a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 niL/min at RT. Purification on normal phase silica gel (EtO Ac/heptane) provided (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-l- (3-(3-methyl-lH-pyrazol-l-yl)-[l, -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate.
Step 5: To a solution of (S)-ethyl 8-(2-amino-6-((R)-2,2;2-trifluoiO-l-(3-(3-methyl-lH-pyrazol- 1 -yl)-[l , -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate (50 mg, 0.08 mmol) from Step 4 in THF (2.0 mL) and water (0,2 mL), was added lithium hydroxide monohydrate (58 mg, 0.05 mmol). The reaction mixture was stirred at RT for 2 h, then the solution was neutralized with 1 N HCl, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided the title compound as an off-white solid as the zwitterionic form.
Example lin: (Si-S-i - mino-e-iiRi-l-fS'^'-dimeth l-S-iS-meth l-lH- razol-l- lJ-fl,!'- biplicnyl]-4-yl)-2>2,2-trifluoroethoxy)pyriniidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
Figure imgf000090_0001
Step J: To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l -(4-bromo-2-(3-metliyl-lH- pyrazol-l -yl)phenyl)-2,2,2-trifiuoi ethoxy)pyrimidin-4-yl)-2J8-diazaspii [4.5]decane-2,3- dicarboxylate (Step 2, Example lu) (300 mg, 0.4 mmol, Step 2) in ethanol (2 mL) and water (0.5 mL) was added (3,4-dimethylphenyl)boronic acid (120 mg, 0.8 mmol), PdCl2(PPh3)2 (41 mg, 0.058 mmol), and Cs2C03 (390 mg, 1.2 mmol). The reaction was heated to 60 °C for 16 h, then cooled to RT, filtered through celite and concentrated in vacuo. Purification by normal phase silica gel column (EtO Ac/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l-(3'J4'- dimethyl-3-(3-methyl-lH-pyrazol-l-yl)-[l,l,-biphenyl]-4-yl)-2,2)2 rifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-2>3-dicarboxylate as a white solid. Step 2: A solution of (S)-2-benzyl 3-ethyl 8-(2-amino~6-((R)-l-(3'34'-dimethyl-3-(3-methyl-lH- pyrazol- 1 -yl)-[l , 1 '-biphenyl]-4-yl)-2J2}2-trifluoi ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-2,3-dicarboxylate (220 mg, 0.3 mmol) in EtOAc (5 mL) was
hydrogenated using an H-Cube apparatus and a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 mL/min at RT. Purification on normal phase silica gel (EtO Ac/heptane) provided (S)-ethyl 8-(2- amino-6-((R)-l-(3*,4,-dimethyl-3-(3-methyl-lH-pyrazol-l-yl)"[l ,l,-biphenyl]-4-yl)-2}2,2- trifluoroethoxy)pyrimidin-4-yl)-258-diazaspiro[4.5]decane-3-carboxyiate. Step 3: To a solution of (S)-ethyl 8-(2-amino-6-((R)-l-(3',4'-dimethyl-3-(3-methyl-lH-pyrazol-l- yl)-[l,r-biphenyl]-4-yl)-2,2,2-trifiuoroethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3- carboxylate (50 mg, 0.08 mmol) from Step 2 in THF (2.0 mL) and water (0.2 mL), was added lithium hydroxide monohydrate (58 mg, 0.05 mmol). The reaction mixture was stirred at RT for 2 h, then the solution was neutralized with 1 N HC1 and concentrated in vacuo. Purification by normal phase silica gel column (EtO Ac/heptane) provided the title compound as an off-white solid as the zwitterionic form.
Example Icq: (Si-S-il-amino^-iiRi- ^^-trifluoro-l-ia'-ihydro meth ^'-methyl-S-iS- methyl-lH-pyrazol-l-yI)-[l,l'-biphenyl]-4-yl)cthoxy)pyrimidin-4-yI)-2,8- diazaspiro[4.5]decane- -carboxylic acid
Figure imgf000091_0001
Step 7: To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l-(4-bromo-2-(3-methyl-lH- pyrazol-l-yl)phenyl)-2,2,2-trifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-2,3- dicarboxylate (Step 2, Example lu) (300 mg, 0.4 mmol, Step 2) in ethanol (2 mL) and water (0.5 mL) was added (3-(hydiOxymethyl)-4-methylphenyl)boronic acid (CAS# 1451391-54-0; 120 mg, 0.7 mmol), PdCl2(PPh )2 (41 mg, 0.058 mmol), and Cs2C03 (390 mg, 1.2 mmol). The reaction was heated to 60 °C for 16 h, then cooled to RT, filtered through celite and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc heptane) provided (S)-2- benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifliioiO-l-(3'-(hydroxymethyl)-4'-methyl-3-(3-methyl- 1 H-pyrazol-1 -yl)-[l , 1 '-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-2,3- dicarboxylate a white solid.
Step 2 A solution of (S)-2~benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoi -l-(3'- (hydroxymethyl)-4,-metliyl-3-(3-methyl-lH-pyrazol-l-yl)-[l,r-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (200 mg, 0.24 mmol,) in EtOAc (5 mL) was hydrogenated using an H-Cube apparatus and a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 mL/min at RT. Purification on normal phase silica gel (EtOAc/heptane) provided (S)-ethyl 8-(2-amino-6-((R)-2}2J2-trifluoi -l-(3'-(hydiOxymethyl)-4'-methyl-3-(3- methyl-lH-pyrazol-l-yl)-[l, -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane- 3-carboxylate.
Step 3: To a solution of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'-(hydiOxymethyl)-4'- methyl-3-(3-methyl-lH-pyrazol-l-yl)-[l,r-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2t8- diazaspiro[4.5]decane-3-caiboxylate (50 mg, 0.08 mmol) from Step 2 in THF (2.0 mL) and water (0.2 mL), was added lithium hydroxide nionohydrate (58 mg, 0.05 mmol). The reaction mixture was stirred at RT for 2 ht then the solution was neutralized with 1 N HC1, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided the title compound as an off-white solid as the zwitterionic form.
Example lcr: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4'-(hydroxymcthyl)-3,-methyI-3-(3- inethyl-lH-pyi'azol-l-yl)-[l,l,-bipheiiyl]-4-yl)ethoxy)pynmidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carl)oxylic acid
Figure imgf000093_0001
The title compound was made as described for (S)-8-(2-amino-6-((R)-2}2,2-trifluoiO-l-(3'- (hydiOxymethyl)-4'-methyl-3-(3-methyl-lH-pyrazol-l-yl)-[l, -biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2J8-diazaspiiO[4.5]decane-3-carboxylic acid (Example Icq) using (4- (hydroxymethyl)-3»methylphenyl)boronic acid (CAS# 1218790-88-5).
Using the generic scheme below, the following examples of Table la were prepared as described above for (S)-8-(2-amino-6-((R)-2,252-trifiuoi -l-(3-(3-methyl-lH-pyrazol-l-yl)-[l,r- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2J8-diazaspiiO[4.5]decane-3-carboxylic acid (Example hi). The boronic acid was generaly used to make the analogues below, however, where it was not available, the corresponding boronate was used.
Figure imgf000093_0002
Table la.
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro- 1 ~(4'- methoxy-3 -(3 -methyl- 1 H-pyrazol- 1 -y 1)- [ 1 , 1 '- lbm 638 bipheny 1 ] -4-yl)ethoxy)py r imidi n- 4-yl) -2, 8 - diazaspiro [4.5] decane-3 -carboxylic acid
(S)-8-(2-amino-6-((R)-l-(4'-ethoxy-3'-fluoiO-3- (3-methyl- 1 H-pyrazol- 1 -yl)-[ 1 , 1 '-biphenyl]-4-
Ibn 670 yl)-2,2,2-trifliioroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro- 1 -(3',4'ί5'- trifluoro-3 -(3 -methyl- 1 H-pyrazol- l-yl)-[l , 1 '- lbo 662 bipheny 1] - 4- y l)ethoxy)py rim idi n- 4-yl)-2 , 8 - diazaspiro[4.5]decane-3-carboxylic acid
(S)-8-(2-amino-6-((R)-l-(3,-chloro-4'-methyl-3- (3 -methyl- 1 H-pyrazol- 1 -yl)-[ 1 , 1 '-biphenyl]-4-
Ibp 657 yl) -2 ,2,2-trifluoro ethoxy)pyrimidin-4 -y 1) -2 , 8 - diazaspiro[4.5]decane-3-carboxylic acid
(S)-8-(2-amino~ό~((R)-2,2)2-trifluolΌ-l-(3,- methyl-3-(3-methyl-l H-pyrazol- l-yl)-4'- lbq (trifluoromethoxy)-[ 1 , 1 '-biphenyl] -4- 706 yl)ethoxy)pyrirnidin-4-yl)-2,8- diazaspiro[4,5]decane-3-carboxylic acid
F (S)-8-(2-ammo-6-((R)-2)2,2-trifluoro-l-(3'- fluoro-5 ' -i soprop oxy- 3 -(3 -methyl- 1 H-pyrazo 1- lbr 684
1 -yl)-[l , 1 '-biphenyl]-4-yl)ethoxy)pyrimidin-4- yl)-2,8-diazaspii [4,5]decane-3 -carboxylic acid
F (S)-8-(2-amino-6-((R)-l-(3,-chloi -5'-fluoiO-3- (3 -methyl- 1 H-pyrazol - 1 -yl [ 1 , 1 '-biphenyl] -4 - lbs 661 yl)-2,2,2-trifluoiOethoxy)pyrimidin-4-yl)-2}8- diazaspiro[4.5]decane-3-carboxylic acid
(S)-8-(2-amino-6-((R)- 1 -(4'-chloro-3-(3- methyl- 1 H-pyrazol - 1 -y 1) -3 ' -(trifluoromethy 1) - lbt
Figure imgf000100_0001
[U'-biphenyl]-4-yl)-2,2,2- 710 trifluoro ethoxy)pyrimidi n-4 -y 1) -2, 8 - diazaspiro[4.5]decane-3-carboxylic acid
(S)-8-(2-amino-6-((R)-2)2,2-trifluoro- 1 -(31- f uoiO-3-(3-methyl-lH-pyiazol-l-yl)-5'- lbu (trifluoromethyl)-[l , 1* -biphen l] -4- 694 yl) ethoxy)pyr i mid i n-4-y 1) -2, 8 - diazaspiro[4.5]decane-3-carboxylic acid
(S)-8-(2-amino-6-((R)-l-(3'-chloi -4'- isopropoxy-3 -(3 -methyl- 1 H-pyrazol- 1 -yl)-[l , - lbv "O biphenyl]-4-yl)-2,2,2- 701 trifluoroethoxy)pyrimid in- 4-y l)-2 , 8 - diazaspiro[4.5]decane-3-carboxylic acid (S)-8-(2-amino-6-((R)-2,2,2-trifluoi -l-(2-(3- methyl- 1 H-pyrazol- 1 -yl)-4-(naphthalen-2~
Ibw 659 yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
(S)-8-(2-amino-6-((R)-l-(4'-(benzyloxy)-3*- fluoro-3 -(3 -methyl- 1 H-pyrazol- 1 -yl)- [ 1 ,1'-
Ibx biphenyl]-4-yl)-2,2,2- 733 trifluoroethoxy)pyrimidin-4 -y 1) -2, 8 - diazaspiro[4.5]decane-3-carboxylic acid
(S)-8-(2-amino-6-((R)-2)2,2-trifluoro-l-(4'- isoprop oxy- 3 '-methyl- 3 -(3 -methyl- 1 H-p razol - lby 681 l-yl)-[l, -biphenyl]-4-yl)ethoxy)pyrimidin-4- yl)-2,8 -di azaspi ro [4.5]decane -3 -c arb oxylic acid
(S)-8-(2-amino-6-((R)-2!2,2-trifluoro-l-(3'- fluoro-3-(3-methyl-lH-pyrazol-l-yl)-4'- lbz propoxy-[ 1 , 1 '-biphenyl]-4-yl)ethoxy)pyrimidin- 685
4-yl)-2,8-diazaspiiO[4.5]decaiie-3-carboxylic
acid
(S)-8-(2-amino-6-((R)-l-(4'-butoxy-3'-fluoi -3- (3 -methyl- 1 H-pyrazol- 1 -yl)- [1,1 '-bipheny 1] -4 - lea 698 yl)-2,2;2-ti,ifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
! (S)-8-(2-amino-6-((R)-2,2;2-trifluoiO-l-(3'- fluoiO-4'-(5-methyl-lJ3,4-oxadiazol-2-yl)-3-(3- leb methyl-1 H-pyrazol- 1 -yl)-[l ,1 '-biphenyl]-4- 709 yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4 , 5 Jdecane -3 -ca boxyli c acid
0 (8)-8-(2-3ηιίηο-6-^)-2,2,2-ΐπ11υοΐΌ-1-(3-(3- methyl-lH-pyrazol-l-yl)-4'-(methylsulfonyl)- lec 687
[l, -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiiO[4.5]decane-3-carboxylic acid
(S)-8-(2-amino-6-((R)-2,2}2-trifmoro-l-(3-(3- methyl- 1 H-pyrazol -1 -yl)-4' -prop oxy- [1 , 1 '- led 668 biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
(S)-8-(2-amino-6-((R)-2)2J2-tnfliioro-l-(3-(3- methyl- 1 H-pyrazol- 1 -yl)-4'-((2-
Ice morpholinoethyl)carbamoyl)-[l , 1 '-biphenyl]-4- 764 yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2~tnfluoiO-l -(3-(3- methyl- 1 H-pyrazol- 1 -yl)-4'-sulfamoyl-[l , 1 '- lef 689 biphenyl] -4-yl)ethoxy)pyrimidin- 4-yl) -2 , 8 - d iazaspiro [4.5 ]decane-3 -carboxylic acid NHj (S)-8-(2-amino-6-(( )-l-(4'-carbamoyl-3-(3- methyl- 1 H-pyrazol- 1 -yl)-[l ,l'-biphenyl]-4-yl)- leg 652
2,2J2-trifluoroethoxy)pyrmiidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3-(3- methyl- 1 H-p razol - 1 -y l)-4'-(methy lc arbamoy 1 ) - lch 666
[1,1 '-biphenyl]-4-yl)e oxy)pyrimidm-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
(S)-8-(2-amino-6-((R)-2}2,2-tnfluoi -l-(3'- fluoro-4'-methoxy-3-(3-methyl-lI-I-pyrazol-l - lci 657 yl)-[l ,1 '-biphenyl]-4-yi)emoxy)pyiimidin-4-yl)- 2,8 -diazaspiro [4.5]decane-3 -carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3-(3- memyl-lH-pyrazol-I -yl)-4'-(piperazine-l- lcj carbonyl)-[l , 1 '-biphenyl]-4- 721 yl)ethoxy)pyrimidin-4-yl)-2J8- di azaspiro [4.5] dec ane- 3 -carboxylic acid
(S)-8-(2-amino-6-((R)~l -(4'- (dimethylcarbamoyi)-3 -(3 -methyl- 1 H-pyrazol - lck l"ylHU )iphenyl]-4-yl)-2,2,2- 680 trifluoiOethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4.5]decane-3-catboxylic acid
(S)-8"(2-amiiio-6-((R)-2,2,2-trifluoiO- 1 -(4'- isobutoxy-3-(3-methyl- 1 H-pyrazol- 1 -yi)-[l ,1 '- lcl 681 biphenyl] -4 -yl)ethoxy)py i'i midin- 4-yl) -2,8- diazaspiiO[4.5]decane-3-carboxylic acid
(S)-8-(2~amino-6-((R)-l-(4'-
(diethyl carbamoyl)-3 -(3 -methyl- 1 H-pyrazol- 1 -
1cm yl)-[l,r-biphenyi]-4-yl)-2,2,2- 707 trifluoioethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-trifluoiO-l -(3-(3- methyl- 1 H-pyrazol- 1 -yl)-4'-(neopentyloxy)- len 695
[1,1 '-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid lco o (S)-8-(2-amino-6-((R 1 -(4-(chroman-6-yl)-2- (3-methyl-l H-pyrazol- 1 -y l)phenyl) -2,2,2-
665 trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
(S)-8-(2-amino-6-((R)-l-(4-(cinnolin-6-yI)-2- (3-methyl- 1 H-pyrazol- 1 -yl)phenyl)-2,2,2- lep 661 trifhioroethoxy)py rim i din-4 -yl) -2, 8 - diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000103_0001
Table lb.
IH NMR Data for Compounds of Table la
Figure imgf000103_0002
6.44 (d, J = 2.3 Hz, 1H), 6.90 (q, J = 6.2 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.75 (d, J = ] 1.7 Hz, 1 H), 7.85 (m, 2H), 7.98 (m, 2H), 8.08 (dt; J = 7.8, 1.3 Hz, 1H), 8.34 (t, J = 1.8 Hz, 1H)
If Ή NMR (400 MHz, MeOH-d4): 5 ppm 1.47 - 1.69 (m, 4 H) 1.97 - 2.13 (m, 1 H) 2.19 - 2.35 (m, 1 H) 2.37 (d, J=0.34 Hz, 0 H) 2.66 - 2.81 (m, 2 H) 3.05 - 3.17 (m, 1 H) 3.18 - 3.28 (m, 1 H) 3.33 - 3.40 (m, 2 H) 3.41 - 3.72 (m, 4 H) 3.73 - 3.83 (m, 2 H) 3.99 - 4.13 (m, 1 H) 5.71 (s, 1 H) 6.32 (d, J=0.39 Hz, 1 H) 6.41 (d, J=2.29 Hz, 2 H) 6.67 - 6.79 (m, 1 H) 7.49 (d, J=1.81 Hz, 1 H) 7.55 - 7.64 (m, 1 H) 7.72 (d, J=8.40 Hz, 2 H) 7.92 (d, J=2.29 Hz, 1 H)
ig ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.49 - 1.69 (m, 4 H) 2.06 (dd, J=13.47, 7.03 Hz, 1 H) 2.31 (dd, J=13.42, 9.32 Hz, 1 H) 2.41 (s, 3 H) 3.12 (d, J=12.00 Hz, 1 H) 3.25 (d, J=l 1.76 Hz, 1 H) 3.38 - 3.57 (m, 2 H) 3.58 - 3.76 (m, 2 H) 4.08 (dd, 1=9.13, 7.17 Hz, 1 H) 5.74 (s, 1 H) 6.44 (d, J=2.34 Hz, 1 H) 6.87 (q, J=6.62 Hz, 1 H) 7.75 - 7.80 (m, 2 H) 7.82 (s, 1 H) 7.89 (s, 2 H) 8,02 (d, J=2.34 Hz, 1 H), 8.57 - 8.69 (m, 2 H)
lh *H NMR (400 MHz, MeOH-d4): δ ppm 1.61 - 1.84 (m, 5 H) 2.10 (dd, J=13.62, 8.49 Hz, 1 H) 2.40 (s, 3 H) 2.47 (dd, J=13.76, 8.88 Hz, 1 H) 3.25 - 3.29 (m, 2 H) 3.73 - 3.91 (m, 4 H) 3.94 (s, 3 H) 4.53 (t, J=8.64 Hz, 1 H) 6.42 (d, J=2,39 Hz, 1 H) 6.81 (q, J=5.94 Hz, 1 H) 7.61 - 7.70 (m, 2 H) 7.71 - 7.78 (m, 1 H) 7.90 - 7.96 (m, 2 H) 8.12 (s, 1 H) li !H NMR (400 MHz, MeOH-d4): δ ppm 1.35 - 1.40 (m, 5 H), 1.60-1.65 (m, 8 H), 2.40 (m, 5 H) 2.47 (dd, J-13.76, 8.88 Hz, 1 H) 3.25 - 3.29 (m, 2 H) 3.73 - 3.91 (m, 4 H) 3.94 (s, 3 H) 4.53 (t, J=8.64 Hz, 1 H), 5.6 (s, 1H), 6.42 (d, J=2.39 Hz, 2 H) 6.70 (m, 1 H) 7.61 - 7.70 (m, 2 H) 7.71 - 7.78 (m, 1 H) 7.90 - 7.96 (m, 2 H) 8.12 (s, 1 H)
ij !H NMR (400 MHz, MeOH-d4): 6 ppm 1.58 - 1.86 (m, 4 H) 2.01 - 2.20 (m, 1 H) 2.40 (s, 3 H) 2.43 - 2.61 (m, 3 H) 3.61 - 3.75 (m, 2 H) 3.86 (s, 4 H) 3.93 (t, J=5.44 Hz, 2 H) 4.25 - 4.37 (m, 2 H) 4.49 - 4.69 (m, 1 H) 6.42 (d, J=2.24 Hz, 2 H) 6.52 (br. s., 1 H) 6.77 - 6.88 (m, 1 H) 7.51 (d, J=1.32 Hz, 1 H) 7.60 - 7.73 (m, 2 H) 7.91 (d, J=2.34 Hz, 1 H) lk Ή NMR (400 MHz, MeOH-d4): δ ppm 1.72 (d, J=18.21 Hz, 4 H) 2.09 (dd, J=13.62, 8.49 Hz, 1 H) 2.18 (d, J=14.50 Hz, 3 H) 2.39 (s, 3 H) 2.48 (dd, J=13.64, 8.91 Hz, 1 H) 2.58 (br. s„ 1 H) 2.66 (br. s., 1 H) 3.60 - 3.95 (m, 6 H) 4,24 (br. s., 2 H) 4.55 (t, J=8.71 Hz, 1 H) 6.33 (br. s., 1 H) 6.42 (d, J=2.34 Hz, 1 H) 6.46 (br. s„ 1 H) 6.75 - 6.87 (m, 1 H) 7.52 (s, 1 H) 7.62 - 7.74 (m, 2 H) 7.92 (d, J=2.34 Hz, 1 H)
11 *H NMR (400 MHz, MeOH-d4): δ ppm 1 ,29 (d, J=6.05 Hz, 6 H) 1.49 (d, J=5.47 Hz, 4 H) 1.70 - 1 ,86 (m, 1 H) 1 ,98 - 2.15 (m, 1 H) 2.37 (s, 3 H) 2.69 (d, J= 11.13 Hz, 1 H) 2.93 (s, 1 H) 3.35 - 3.52 (m, 2H) 3.53 - 3.64 (m, 2 H) 3.64 - 3.73 (m, 1 H) 4.59 (s, 1 H) 5.71 (s, 1 H) 6.38 (d, J=2.15 Hz, 1 H) 6.68 - 6.82 (m, 1 H) 6.93 (d, J=8.79 Hz, 2 H) 7.44 - 7.58 (m, 3 H) 7.64 (d, J=1.37 Hz, 1 H) 7.67 - 7.78 (m, 1 H) 7,93 (d, J=2.15 Hz, 1 H) lm ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.51 (d, J=5.47 Hz, 4 H) 1.71 - 1.86 (m, 1 H) 2.01 - 2.17 (m, 1 H) 2,28 (s, 3 H) 2.31 (s, 3 H) 2.39 (s, 3 H) 2.64 - 2.78 (m, 1 H) 2.90 - 3.05 (in, 1 H) 3.36 - 3.54 (m, 2 H) 3.55 - 3.79 (m, 3 H) 5.73 (s, 1 H) 6.41 (d, J=2.15 Hz, 1 H) 6.69 - 6.87 (m, 1 H) 7.20 (s, 1 H) 7.33 - 7.40 (m, 1 H) 7.43 (s, 1 H) 7.59 (d, J=1.37 Hz, 1 H) 7.70 (s, 1 H) 7.75 (s, 1 H) 7.96 (d,J=2.15 Hz, 1 H)
In !H NMR (400 MHz, MeOH-d4): 5 ppm 1.53 (d, J=5.86 Hz, 4 H) 1.75 - 1.87 (m, 1 H) 2.04 - 2.17 (m, 1 H) 2.41 (s, 3 H) 2.64 - 2.76 (m, 1 H) 2.91 - 3.04 (m, 1 H) 3.38 - 3.54 (m, 2 H) 3.55 - 3.74 (m, 3 H), 3.95 (s, 3 H) 5.72 (s, 1 H) 6.44 (d, J=2.34 Hz, 1 H) 6.79 - 6.92 (m, 1 H) 7.12 (s, 1 H) 7.23 - 7.31 (m, 1 H) 7.74 (d, J=1.17 Hz, 1 H) 7.79 - 7.89 (m, 2 H) 8.02 (d, J=2.15 Hz, 1 H) 8.15 - 8.25 (m, 1 H) lo *H NMR (400 MHz, MeOH-d4): δ ppm 1.60 (br. s., 4 H) 2.02 - 2.17 (m, 1 H) 2.24 -
2.39 (m, 1 H) 2.43 (s, 3 H) 2.53 - 2.66 (m, 4 H) 3.07 - 3.17 (m, 1 Η) 3.21 - 3.29 (m, 1 H)
3.40 - 3.59 (m, 2 H) 3.61 - 3.80 (m, 2 H) 4.00 - 4.18 (m, 1 H) 5.77 (s, 1 H) 6.45 (d, J=2.15 Hz, 1 H) 6.75 - 6.90 (m, 1 H) 7.36 - 7.56 (m, 1 H) 7.73 (d, J=4.10 Hz, 2 H) 7.77 - 7.89 (m, 4 H) 8.01 (d, J=2.15 Hz, 1 H)
1p Ή NMR (400 MHz, MeOH-d4): δ ppm 1.24 - 1.42 (m, 9 H) 1.60 (br. s. , 4 H) 2.02 - 2.12 (m, 1 H) 2.42 (s, 4 H) 3.05 - 3.17 (m, 1 H) 3.20 - 3,29 (m, i H) 3.41 - 3.79 (m, 4 H) 4.02 - 4.17 (m, 1 H) 5.78 (s, ί H) 6.43 (d, J=2.15 Hz, 1 H) 6.73 - 6.88 (m, 1 H) 7.51 (d, J=8.40 Hz, 2 H) 7.57 - 7.69 (m, 3 H) 7.78 (s, 2 H) 7.98 (d, J=2.15 Hz, Ϊ H)
lq lH NMR (400 MHz, MeOH-d4): δ ppm 1.41 (t, J=7.03 Hz, 3 H) 1.60 (br. s„ 4 H) 1.95 - 2.14 (m, 1 H) 2.27 - 2.38 (m, ί H) 2.41 (s, 3 H) 3.14 (s, 1 H) 3.20 - 3.29 (m, 1 H) 3.41 - 3.59 (m, 2 H) 3.60 - 3.83 (m, 2 H) 3.99 - 4.20 (m, 3 H) 5.77 (s, 1 H) 6.43 (d, J=2,34 Hz, 1 H) 6.71 - 6.85 (m, 1H) 7.00 (d, J=8.79 Hz, 2 H) 7.52 - 7.65 (m, 3 H) 7.72 (d, J=l .56 Hz, 1 H) 7.76 (s, 1 H) 7.97 (d, J-2.34 Hz, 1 H)
Il¬ 'H NMR (400 MHz, MeOH-d4): δ ppm 1.62 (d, J=4.88 Hz, 4 H) 2.02 - 2.13 (m, 1 H) 2.27 - 2.38 (m, 1 H) 2.42 (s, 3 H) 3.16 (s, 1 H) 3.26 (s, 1H) 3.41 - 3.59 (m, 2 H) 3.60 - 3.78 (m, 2 H) 3.99 - 4.19 (m,4 H) 5.76 (s, 1 H) 6.45 (d, J=2.34 Hz, 1 H) 6,82 - 6.96 (m, 1 H) 7.74 (d, J=1.56 Hz, 1 H) 7.81 (d, J-1.56 Hz, 1 H) 7.86 (s, 1 H) 8.03 (d, J=2.15 Hz, 1 H) 8.92 (s, 2 H))
ls ¾ NMR (400 MHz, MeOH-d4): δ ppm 1 ,59 (br. s., 4 H) 2.01 - 2.14 (m, 1 H) 2.31 (br. s., 1 H) 2.41 (s, 3 H) 3.07 - 3.17 (m, 1 H) 3.21 - 3.29 (m, 1 H) 3.40 - 3.59 (m, 2 H) 3.67 (d, J=5.47 Hz, 2 H) 3.95 (s, 3 H) 4.09 (d, J=1.17 Hz, 1 H) 5.75 (s, 1 H) 6.43 (d, J=2.15 Hz, 1 H) 6.82 (d, J=6.44 Hz, 1 H) 6,88 (d, J=8.79 Hz, 1 H) 7.64 (d, J=1.56 Hz, 1 H) 7.68 - 7.76 (m, 1 H) 7.77 - 7.87 (m, 1 H) 7.93 - 8.07 (m, 2 H) 8,45 (d, J=2.34 Hz, 1 H) hi Ή NMR (400 MHz, MeOH-d4): 5 ppm 1.42 - 1.74 (m, 4 H) 2.05 (dd, J=13.50, 7.20 Hz, 1 H) 2.40 (s, 4 H) 3.07 - 3.16 (m, 1 H) 3.17 - 3.29 (m, 1 H) 3.38 - 3.59 (m, 2 H) 3.59 - 3.78 (m, 2 H) 4.11 (dd, J=9.10, 7.25 Hz, 1 H) 6.42 (d, J=2,34 Hz, 1 H) 6.74 - 6.86 (m, 1 H) 7.34 - 7.41 (m, 1 H) 7.42 - 7.50 (m, 2 H) 7.60 - 7.69 (m, 3 H) 7.71 - 7.77 (m, 1 H) 7.77 - 7.83 (m, 1 H) 7.97 (d, J=2.00 Hz, 1 H)
lv !H NMR (400 MHz, MeOH-d4): δ ppm 1.24 (t, J=7.59 Hz, 3 H) 1.50 - 1.69 (m, 4 H) 2.06 (dd, J=13.42, 7.13 Hz, 1 H) 2,32 (dd, J=13.45, 9.20 Hz, 1 H) 2.37 (s, 3 H) 2.72 (q, J=7.61 Hz, 2 H) 3.08 - 3.27 (m, 2 H) 3.39 - 3.78 (m, 4 H) 4.08 (dd, J=9.13, 7.17 Hz, 1 H) 5.74 (s, 1 H) 6,36 (d, J=2.34 Hz, 1 H) 6.71 (q, J=6.65 Hz, 1 H) 7.26 - 7.34 (m, 1 H) 7,35 - 7.44 (m, 1 H) 7.56 (s, 1 H) 7.82 (d, J=2.29 Hz, 1 H)
lw lU NMR (400 MHz, MeOH-d4): δ ppm 1.51 - 1.64 (m, 4 H) 1 ,96 (s, 2 H) 2.04 (dd, JM13.23, 7.32 Hz, 1 H) 2.25 - 2.34 (m, 1 H) 2.38 (s, 3 H) 3.09 (d, J=l 1.67 Hz, 1 H) 3.23 (d, J=l 1.81 Hz, 1 H) 3.38 - 3.56 (m, 2 H) 3.59 - 3.73 (m, 2 H) 4.00 - 4.10 (m, 1 H) 5.73 (s, 1 H) 6.41 (d, J=2.34 Hz, 1 H) 6.79 - 6.89 (m, 1 H) 7.61 - 7.67 (m, 1 H) 7.69 - 7.88 (m, 4 H) 7.96 - 8.02 (m, 2 H) 8.08 (t, J=1.59 Hz, 1 H)
lx ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.49 - 1.64 (m, 4 H) 1.97 (s, 3 H) 1.98 (s, 3 H) 2.04 (dd, J=13.35, 7.15 Hz, 1 H) 2.29 (dd, J=13.47, 9.18 Hz, 1 H) 2.38 (s, 3 H) 3.05 - 3.26 (m, 2 H) 3.39 - 3.73 (m, 4 H) 4.05 (dd, JM9.18, 7.22 Hz, 1 H) 4.38 (s, 2 H) 5.73 (s, 1 H) 6.40 (d, J=2.29 Hz, 1 H) 6.77 (q, J=6.67 Hz, 1 H) 7.37 (d, J=8.40 Hz, 2 H) 7.59 - 7.66 (m, 3 H) 7.71 - 7.81 (m, 2 H) 7.95 (d, J=2.34 Hz, 1 H)
Ή NMR (400 MHz, MeOH-d4): δ ppm 1.57 (t, J=4.44 Hz, 4 H) 1.89 (s, 3 H) 1.97 (s, 4 H) 2.04 (dd, J=13.37, 7.13 Hz, 1 H) 2.29 (dd, J-13.28, 9.18 Hz, 1 H) 2.38 (s, 3 H) 2.82 (t, J=7.32 Hz, 2 H) 3.06 - 3.25 (m, 2 H) 3.40 (t, J=7.32 Hz, 2 H) 3.43 - 3.73 (m, 4 H) 4.05 (dd, J=9.18, 7.27 Hz, 1 H) 5.74 (s, 1 H) 6.40 (d, J=2.25 Hz, 1 H) 6.77 (q, J=6.80 Hz, 1 H) 7.31 (d, J=8.30 Hz, 2 H) 7.57 - 7.63 (m, 3H) 7.70 - 7.80 (m, 2 H) 7.95 (d, J=2.34 Hz, 1 H)
lz 'H NMR (400 MHz, MeOH-d4): δ ppm 1.53 - 1.61 (m, 4 H) 1.97 (s, 3 H) 2.04 (dd, J=13.32, 7.03 Hz, 1 H) 2,30 (dd, J=13.59, 9.30 Hz, 1 H) 2.40 (s, 3 H) 3.06 - 3.26 (m, 2 H) 3.40 - 3.72 (m, 4 H) 4.06 (dd, J=8.91, 7.25 Hz, 1 H) 5.76 (s, 1 H) 6.42 (d, J=2.29 Hz, 1 H) 6.85 (q, J=6.51 Hz, 1 H) 7.55 (dd, J=8.27, 4.32 Hz, 1 H) 7.82 (d, J=1.71 Hz, 1 H) 7.85 - 7.99 (m, 3 H) 8.00 - 8.07 (m, 2 H) 8.29 (s, 1 H) 8.39 (d, J=7.61 Hz, 1 H) 8.88 (dd, J=4.30, 1.66 Hz, 1 H)
laa Ή NMR (400 MHz, MeOH-d4): δ ppm 1.59 (d, J=4.69 Hz, 4 H) 1.99 - 2.13 (m, 1 H) 2.24 - 2.39 (m, 1 H) 3.03 - 3, 14 (m, 1 H) 3.17 - 3.27 (m, 1 H) 3.38 - 3.54 (m, 2 H) 3.55 - 3.75 (m, 2 H) 3.99 - 4.14 (m, 1 H) 5.56 (s, 1 H) 6.46 (d, J=2.93 Hz, 1 H) 6.58 - 6.71 (m, 1 H) 7.27 (d, J=3.12 Hz, 1 H) 7.29 - 7.36 (m, 1 H) 7.54 - 7.66 (m, 4 H) 7.70 (d, J=8.20 Hz, 2 H)
lab Ή NMR (400 MHz, MeOH-d4): δ ppm 1 ,52 - 1.62 (m, 4 H) 1.92 (s, 5 H) 1.99 - 2,09 (m, 1 H) 2.27 (dd, J=13.42, 9.22 Hz, 1 H) 2.38 (s, 3 H) 3.06 - 3.26 (m, 2 H) 3.39 - 3,73 (m, 4 H) 4.00 - 4,08 (m, 1 H) 4.13 (s, 2 H) 5.72 (s, 1 H) 6.41 (d, J=2.29 Hz, 1 H) 6.78 (q, J=6.49 Hz, 1 H) 7.53 (d, J=8.30 Hz, 2 H) 7.66 (d, J=1.66 Hz, 1 H) 7,73 - 7.84 (m, 4 H) 7.97 (d, J=2.25 Hz, 1 H)
lac 'H NMR (400 MHz, MeOH-d4): δ ppm 1.51 - 1 ,70 (m, 4 H) 2.06 (dd, J=13.37, 7.13 Hz, 1 H) 2.31 (dd, J=13.28, 9,37 Hz, 1 H) 2.41 (s, 3 H) 3.08 - 3.19 (m, 1 H) 3.20 - 3,29 (m, 1 H) 3.39 - 3.78 (m, 4 H), 4.01 - 4.19 (m, 1 H) 5.75 (s, 1 H) 6.43 (d, J=2.15 Hz, 1 H) 6.84 (d, J=6.64 Hz, 1 H) 7,06 - 7.19 (m, 1 H) 7,37 - 7.52 (m, 3 H) 7.65 (d, J=l ,56 Hz, 1 H) 7,70 - 7.77 (m, 1 H) 7.78 - 7.86 (m, 1 H) 8.00 (d, J=2.15 Hz, 1 H)
l ad Ή NMR (400 MHz, MeOH-d4): 8 ppm 1.53 - 1.68 (m, 4 H) 2.00 - 2.11 (m, 1 H) 2,25 - 2.36 (m, 1 H) 2,44 (s, 3 H) 3.03 - 3, 13 (m, 1 H) 3.18 - 3.26 (m, 1 H) 3.42 - 3.60 (m, 2 H) 3.62 - 3.80 (m, 2 H) 3.98 - 4.12 (m, 1 H) 5,73 - 5.86 (m, 1 H) 6,38 - 6.53 (m, 1 H) 6.80 - 6.96 (m, 1 H) 7.56 - 7.64 (m, 1 H) 7.82 - 7.93 (m, 2 H) 7.93 - 8.00 (m, 1 H) 8.03 - 8.09 (m, 1 H) 8.16 (s, 2 H) 8.28 - 8.38 (m, 1 H), 8.42 - 8.55 (m, 1 H) 8.80 - 8.97 (m, 1 H) lae Ή NMR (400 MHz, MeOH-d4): δ ppm 0.89 (t, J = 6.7 Hz, 1H), 1.30 (d, J = 16.8 Hz, 3H), 1.57 (q, J = 8.1, 5.5 Hz, 4H), 1.98 (m, 1H), 2.24 (m, 1H), 2.38 (d, J = 10.5 Hz, 6H), 2.99 (d, J = 1 1.6 Hz, 1H), 3.16 (d, J = 11.5 Hz, 1H), 3.48 (ddt, J = 20.2, 13.1, 6.1 Hz, 3H), 3.65 (dd, J = 13.9, 6.2 Hz, 2H), 3.96 (t, J = 8.0 Hz, 1H), 5.75 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.77 (q, J = 6.6 Hz, 1H), 7.26 (d, J = 7.8 Hz, 2H), 7.58 (m, 3H), 7.74 (m, 2H), 7.96 (d, J = 2.4 Hz, 1H)
l af 1H NMR (400 MHz, MeOH-d4): δ ppm 0,90 (m, 1H), 1.27 (m, 5H), 1.51 (dt, J - 10.5, 5.6 Hz, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.09 (dd, J = 13.1, 8.7 Hz, I II), 2.40 (s, 3H), 2.76 (d, J = 11.0 Hz, 1H), 2.90 (d, J = 1 1 ,0 Hz, 1H), 3.54 (m, 4H), 3,84 (dd, J = 8,7, 7.2 Hz, 1H), 4.19 (qd, J = 7.1, 1.7 Hz, 2H), 5.73 (s, 1H), 6.43 (d, J = 2.4 Hz, 1H), 6.84 (q, J = 6.5 Hz, 1H), 7.64 (m, 3H), 7.80 (m, 3H), 8.01 (d, J = 2.4 Hz, 1H) lag Ή NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 14.8 Hz, 1H), 1.58 (s, 8H), 2.05 (m, 2H), 2.39 (s, 8H), 3.12 (d, J = 1 1.1 Hz, 2H), 3.24 (d, J = 11.2 Hz, 3H), 3.47 (s, 3H), 3.53 (s, 1H), 3.64 (s, 4H), 4.11 (s, 2H), 4.96 (s, 1H), 6.42 (d, J = 2.0 Hz, 2H), 6.83 (q, J = 6.6 Hz, 2H), 7.33 (q, J = 9.0 Hz, 2H), 7.47 (t, J = 6.1 Hz, 2H), 7.65 (m, 6H), 7.79 (d, J = 8.1 Hz, 2H), 7.99 (d, J = 2.0 Hz, 2H) lah !H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 10.2 Hz, 1H), 1.57 (t, J = 5.3 Hz, 5H), 2.04 (dd, J = 13.2, 6.9 Hz, 1H), 2.34 (m, 5H), 3.09 (d, J = 11.8 Hz, 1H), 3.22 (m, 2H), 3.48 (dd, J - 25.5, 12.5 Hz, 3H), 3.64 (s, 3H), 4.06 (t, J = 7.9 Hz, 1H), 4.83 (s, 2H), 4.93 (s, 1H), 5.74 (s, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.81 (q, J = 6.7 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.65 (m, 3H), 7.76 (m, 3H), 7.98 (d, J = 2.3 Hz, 1H)
lai Ή NMR (400 MHz, MeOH-d4); δ ppm 0.91 (tt, J = 8,8, 4,7 Hz, 1H), 1.32 (m, 3H), 1.58 (h, J = 5.2, 4.4 Hz, 8H), 1 ,99 (m, 2H), 2.25 (dd, J = 13.4, 9.0 Hz, 2H), 2.40 (s, 6H), 3.03 (d, J = 11.5 Hz, 2H), 3.18 (d, J = 11.5 Hz, 2H)} 3.48 (ddt, J = 21.1, 13.0, 5.9 Hz, 5H), 3.62 (dt, J = 11.3, 6.3 Hz, 4H), 3.98 (t, J = 7.9 Hz, 2H), 5.73 (s, 2H), 6,44 (d, J - 2.4 Hz, 2H), 6.90 (q, J = 6.6 Hz, 2H), 7.86 (m, 6H), 8.04 (d, J = 2.4 Hz, 2H), 9.15 (d, J = 11.9 Hz, 6H)
lak !H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 1.67 (dt, J = 11.3, 5.3 Hz, 4H), 2,08 (dd, J = 13,6, 8.1 Hz, 1H), 2.40 (m, 4H), 3.25 (q, J = 11.8, 9.3 Hz, 3H), 3.67 (m, 4H), 4.43 (t, J = 8,5 Hz, IH), 6.44 (d, J = 2.4 Hz, 1H), 6.95 (q, J = 6.3 Hz, 1H), 7,77 (dt, J = 5.4, 1,8 Hz, 2H), 7.86 (d, J = 1 A Hz, 2H), 7.96 (m, 1H), 8.05 (d, J = 2.4 Hz, 2H) lal Ή NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 1.44 (t, J = 7.0 Hz, 3H), 1.57 (t, J = 5,6 Hz, 4H), 2.02 (dd, J = 13.4, 7.0 Hz, 1H), 2.28 (dd, J - 13.3, 9.1 Hz, 1H), 2.39 (s, 3H), 3.06 (d, J = 11.6 Hz, 1H), 3.21 (d, J = 11.6 Hz, IH), 3.47 (dd, J = 22.4, 13.7 Hz, 3H), 3.65 (dd, J = 13.8, 6.9 Hz, 2H), 4.03 (t, J = 8.1 Hz, 1H), 4.14 (q, J = 7.0 Hz, 2H), 4.93 (s, 2H), 5,75 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.78 (q, J = 6.6 Hz, 1H), 7.12 (d, J = 8.7 Hz, 1H), 7.57 (m, 2H), 7.73 (m, 3H), 7.98 (d, J = 2.4 Hz, 1H)
lam Ή NMR (400 MHz, MeOH-d4): 8 ppm 1.29 (d, J = 3.7 Hz, 2H), 1.55 (m, 4H), ,92 (dd, J = 13.4, 7.2 Hz, IH), 2.19 (t, J = 10.6 Hz, 1H), 2,40 (s, 3H), 2.88 (d, J = 11.4 Hz, 1H), 3.10 (d, J = 11.5 Hz, IH), 3.47 (dd, J = 22.2, 15.6 Hz, 3H), 3.64 (s, 3H), 3.85 (t, J = 8.1 Hz, IH), 5.74 (s, IH), 6.43 (d, J = 2.4 Hz, IH), 6.83 (q, J = 6.6 Hz, IH), 7.69 (m, 3H), 7.82 (m, 2H), 7.99 (m, 3H)
Ian Ή NMR (400 MHz, MeOH-d4): δ ppm 1.17 (t, J = 7.0 Hz, IH), 1.29 (m, IH), 1.57 (d, J = 5.9 Hz, 4H), 2.00 (dd, J = 13.4, 7.0 Hz, IH), 2.26 (dd, J = 13,1, 9.4 Hz, IH), 2.38 (d, J = 9.1 Hz, 6H), 3.03 (d, J = 11.6 Hz, IH), 3.18 (d, J = 11.5 Hz, IH), 3,47 (ddt, J = 20.8, 13.2, 6.0 Hz, 2H), 3.62 (h, J = 7.1, 6.4 Hz, 3H), 4.00 (t, J = 7.9 Hz, IH), 4.89 (s, 9H), 5.74 (s, IH), 6.41 (d, J = 2.3 Hz, IH), 6.82 (q, J = 6.9, 6.4 Hz, IH), 7.21 (s, IH), 7.40 (s, IH), 7.45 (s, IH), 7.60 (d, J = 1.9 Hz, IH), 7.68 (dd, J = 8.0, 1.8 Hz, IH), 7.78 (d, J = 8.2 Hz, IH), 7.99 (d, J = 2.3 Hz, IH)
lao !H NMR (400 MHz, MeOH-d4): 6 ppm 1 ,28 (m, 2H), 1.55 (q, J = 7.5, 5.1 Hz, 4H), 1.94 (dd, J = 13.2, 6.9 Hz, 1H), 2.21 (dd, J = 13.1, 8.9 Hz, IH), 2.39 (s, 3H), 2.94 (d, J = 11.5 Hz, lH), 3.12 (d, J = 11.2 Hz, IH), 3.46 (ddt, J = 20.2, 13.0, 5.9 Hz, 2H), 3.63 (dd, J = 13.7, 6.1 Hz, 2H), 3.90 (t, J = 8.0 Hz, IH), 4.85 (d, J = 9.0 Hz, IH), 5.73 (s, IH), 6,42 (d, J = 2.4 Hz, IH), 6.83 (q, J = 6.6 Hz, IH), 7.57 (m, 4H), 7.77 (m, 2H), 8.00 (d, J = 2.4 Hz, IH)
lap Ή NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J - Π .9 Hz, 2H), 1.39 (t, J = 7.0 Hz, 3H), 1.59 (t, J = 5.7 Hz, 4H), 2,05 (dd, J = 13.4, 7.2 Hz, IH), 2.39 (s, 4H), 3.12 (d, J = 1 1.6 Hz, lH), 3.24 (d, J = 1 1.7 Hz, IH), 3.51 (ddt, J = 25.1, 13,2, 5.8 Hz, 2H), 3.67 (dd, J = 13.8, 5.7 Hz, 2H), 4.10 (dq, J = 14.0, 7.7, 7.0 Hz, 3H), 6.41 (d, J = 2.3 Hz, IH), 6,79 (q, J = 6.6 Hz, H), 6.93 (dd, J = 8.2, 2.5 Hz, IH), 7.1 (m, 2H), 7.34 (t, J = 7.9 Hz, IH), 7.62 (d, J = 1.8 Hz, IH), 7.75 (m, 2H), 7.97 (d, J = 2.4 Hz, IH) l aq Ή NMR (400 MHz, MeOH-d4): δ ppm 0,89 (t, J = 7.2 Hz, IH), 1 ,28 (s, 4H), 1.58 (t, J = 5.6 Hz, 4H), 2.05 (dd, J = 13.5, 7.1 Hz, IH), 2.29 (d, J = 1.8 Hz, 4H), 2,39 (s, 3H), 3.10 (d, J = 1 1.8 Hz, IH), 3.24 (d, J = 1 1.5 Hz, IH), 3.49 (ddt, J = 21.1, 12.9, 5.8 Hz, 311), 3.68 (ddt, J = 18.9, 12.4, 6.2 Hz, 3H), 4.07 (m, IH), 5.75 (s, IH), 6,41 (d, J = 2.3 Hz, IH), 6,80 (q, J = 6.5 Hz, IH), 7.37 (m, 3H), 7.63 (d, J = 1.8 Hz, IH), 7.76 (m, 2H), 7.98 (d, J = 2.3 Hz, IH)
1 alΉ NMR (400 MHz, MeOH-d4): δ ppm 1.57 (t, J = 5.8 Hz, 4H), 1.99 (dd, J = 13.3, 7.0 Hz, 1H), 2.25 (dd, J = 13,3, 9.1 Hz, IH), 2.39 (s, 3H), 3.00 (d, J = 11.3 Hz, lH), 3.17 (d, J = 1.5 Hz, IH), 3.31 (d, J - 2.4 Hz, 4H), 3.49 (m, 2H), 3.65 (dd, J = 13.8, 6.6 Hz, 2H), 3.97 (t, J = 8.1 Hz, IH), 5.74 (s, IH), 6.42 (d, J = 2,3 Hz, IH), 6.83 (q, J = 6.6 Hz, IH), 7.33 (t, J = 8.8 Hz, IH), 7,65 (m, 2H), 7.73 (dd, J = 8.2, 1.9 Hz, IH), 7.82 (m, 2H), 8.00 (d, J = 2,3 Hz, IH) i s Ή NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, IH), 1.60 (m, 4H), 2.05 (dd, J = 13.4, 7.1 Hz, H), 2.32 (dd, J = 13.4, 9.1 Hz, IH), 2.40 (s, 3H), 3.12 (d, J = 11.7 Hz, IH), 3.24 (d, J = 11 .7 Hz, IH), 3.51 (dq, J = 24,6, 7.3, 6.5 Hz, 2H), 3.66 (dt, J = 11 ,7, 6.2 Hz, 2H), 4.1 1 (dd, J = 9.1, 7.1 Hz, IH), 6.42 (d, J = 2.3 Hz, 1H), 6.83 (q, J = 6.3 Hz, IH), 7.32 (m, IH), 7.58 (dd, J = 1 .5, 7.5 Hz, 2H), 7.69 (m, 2H), 7.80 (m, 2H), 8.01 (d, J = 2.3 Hz, IH) lat ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, IH), 1.57 (m, 4H), 1.97 (dd, J = 13.1, 6.8 Hz, IH), 2.23 (m, 2H), 2.37 (d, J = 18,2 Hz, 9H), 2.98 (d, J = 11.6 Hz, IH), 3.15 (d, J = 1 1.5 Hz, IH), 3.48 (ddt, J = 20.5, 13.0, 5.8 Hz, 2H), 3.65 (dd, J = 13.4, 5.8 Hz, 2H), 3.94 (dd, J = 9.1 , 7.1 Hz, IH), 5.75 (s, IH), 6.41 (d, J = 2.3 Hz, IH), 6.78 (q, J = 6.6 Hz, IH), 7.03 (s, IH), 7.27 (d, J = 1.6 Hz, 2H), 7,59 (d, J = 1.8 Hz, Hi), 7.73 (m, 2H), 7,97 (d, J = 2,4 Hz, IH) lau lH NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 3.4 Hz, 2H), 1.60 (t, J = 5.7 Hz, 4H), 2.06 (dd, J = 13.5, 7.2 Hz, IH), 2.39 (s, 4H), 3.13 (d, J = 11.7 Hz, IH), 3.25 (d, J = 1 .7 Hz, IH), 3.52 (m, 2H), 3.67 (dt, J = 12.0, 6.4 Hz, 2H), 4.14 (dd, J = 9.1, 7.2 Hz, 1 II), 4.91 (s, 1H), 6.42 (d, J = 2.4 Hz, IH), 6.83 (q, J = 6.6 Hz, 1H), 7.36 (dt, J - 10.4, 8.4 Hz, IH), 7.51 (ddt, J = 8.1 , 3.9, 1.6 Hz, IH), 7.65 (m, 2H), 7.77 (m, 2H), 7.99 (d, J = 2.3 Hz, IH)
l v Ή NMR (400 MHz, MeOH-d4): δ ppm 1.57 (dt, J - 6.7, 3.0 Hz, 4H), 1.98 (dd, J =
13.3, 7.0 Hz, IH), 2,24 (dd, J = 13.4, 9.2 Hz, 1H), 2.40 (s, 3H), 2.99 (d, J = 1 1.5 Hz, IH), 3.16 (d, J = 11.5 Hz, IH), 3.48 (ddt, J = 20.5, 13.2, 5.9 Hz, 2H), 3.65 (dq, J = 11.1, 5.0 Hz, 2H), 3.95 (t, J = 8.2 Hz, IH), 5.74 (s, IH), 6.42 (d, J = 2.4 Hz, IH), 6.84 (q, J = 6.6 Hz, IH), 6.99 (tt, J = 9.0, 2,3 Hz, IH), 7.35 (m, 2H), 7.68 (d, J = 1.9 Hz, IH), 7.79 (m, 2H), 8.02 (d, J = 2.4 Hz, IH)
l w ¾ NMR (400 MHz, MeOH-d4): δ ppm 0.89 (m, IH), 1 ,30 (d, J = 13.3 Hz, 2H), 1.51 (q, J = 6.5, 5.7 Hz, 5H), 1.77 (dd, J = 13.0, 6.9 Hz, IH), 2.05 (dd, J = 13.0, 8.9 Hz, IH), 2.40 (s, 3H), 2.62 (d, J = 11 ,0 Hz, IH), 2.93 (d, J = 11.0 Hz, IH), 3.42 (d, J = 14,2 Hz, 2H), 3.49 (s, IH), 3,62 (dt, J = 16.7, 6.6 Hz, 3H), 5.72 (s, IH), 6.42 (d, J = 2.4 Hz, IH), 6,83 (q, J = 6.6 Hz, IH), 7,44 (m, IH), 7.69 (d, J = 1.9 Hz, IH), 7.81 (m, 2H), 8.01 (m, 3H) lax *H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (m, 2H), 1.32 (m, 13H), 1.57 (t, J = 5.4 Hz, 4H), 2,01 (m, IH), 2.29 (dd, J = 13.4, 9.2 Hz, IH), 2.39 (s, 3H), 2.80 (s, IH), 3.07 (d, J = 1 1 ,6 Hz, IH), 3.17 (s, IH), 3.50 (m, 2H), 3.66 (d, J = 13.8 Hz, 2H), 4.03 (t, J = 8.1 Hz, IH), 4.65 (p, J = 6.1 Hz, IH), 5.75 (s, IH), 6.41 (d, J = 2.4 Hz, IH), 6.78 (q, J = 6.6 Hz, I H), 7.16 (t, J = 8.6 Hz, IH), 7.45 (m, 2H), 7.61 (d, J - 1.8 Hz, IH), 7.74 (m, 2H), 7.98 (d, J = 2.4 Hz, IH) lay Ή NMR (400 MHz, MeOH~d4): δ ppm 0.88 (m, 2H), 1.28 (s, 2H), 1.39 (t, J = 7.0 Hz, 3H), 1.59 (d, J = 5.6 Hz, 4H), 2.04 (dd, J = 13.5, 7.1 Hz, IH), 2.39 (s, 4H), 3.10 (d, J = 11.7 Hz, lH), 3.24 (m, IH), 3,49 (ddt, J = 25.3, 13,1, 5.9 Hz, 2H), 3.66 (dq, J = 12.1, 5.6 Hz, 2H), 4.07 (dq, J = 12.7, 7,2 Hz, 3H), 5.75 (s, IH), 6.42 (d, J = 2.4 Hz, IH), 6.71 (dt, J = 10.8, 2.2 Hz, IH), 6.80 (p, J = 6.6 Hz, IH), 7.01 (m, 2H), 7.63 (d, J = 1.8 Hz, IH), 7.76 (m, 2H), 8,00 (d, J - 2.4 Hz, IH)
Ή NMR (400 MHz, MeOH-d4): 6 ppm 0.90 (m, IH), 1.36 (s, 13H), 1.59 (m, 4H), 2.05 (dd, J = 13.4, 6.9 Hz, IH), 2.33 (dt, J = 13.7, 6.0 Hz, IH), 2,40 (s, 3H), 3.12 (d, J = 1 1.4 Hz, IH), 3.24 (d, J = 12.1 Hz, IH), 3.40 (s, IH), 3.53 (d, J = 14.7 Hz, IH), 3.68 (d, J = laz 13.4 Hz, 2H), 4.10 (s, IH), 4.76 (m, 5H), 4.83 (s, 2H), 5.01 (s, IH), 6.42 (d, J = 2.2 Hz, IH), 6.77 (q, J = 6.6 Hz, HI), 7.42 (m, 3H), 7.65 (m, 4H), 7.76 (m, 2H), 7.98 (d, J = 2.3 Hz, IH)
lH NMR (400 MHz, MeOH-d4): δ ppm 1,30 (d, J = 12.1 Hz, 3H), 1.59 (t, J = 5.2 Hz, lba 4H), 2,05 (dd, J = 13.4, 7.0 Hz, IH), 2,34 (m, 7H), 3.11 (d, J = 11.7 Hz, IH), 3.24 (d, J = 11.8 Hz, IH), 3.51 (m, 2H), 3.68 (dt, J = 13.1, 6.3 Hz, 2H), 4.09 (dd, J = 9.2, 6.9 Hz, IH), 6.41 (d, J = 2.3 Hz, IH), 6.79 (q, J = 6.7 Hz, IH), 7.11 (t, J = 9.1 Hz, IH), 7.55 (m,
Figure imgf000110_0001
'H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1 H), 1 .59 (d, J = 5.4 Hz, 4H), 2.04 (dd, J = 13.4, 7.0 Hz, 1 H), 2.29 (m, 2H), 2.41 (d, J = 9.6 Hz, 9H), 3.10 (d, J = 1 1.7 Hz, 1 H), lbh 3.24 (m, 1H), 3.49 (ddt, J = 20.7, 13.0, 6.0 Hz, 2H), 3.65 (dt, J = 13.2, 7.2 Hz, 2H), 4.06 (dd, J = 9.2, 7.1 Hz, IH), 5.75 (s, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.79 (q, J = 6.6 Hz, IH), 7.45 (s, 2H), 7.62 (d, J = 1.8 Hz, IH), 7.75 (m, 2H), 7.98 (d, J = 2.4 Hz, IH)
Ή NMR (400 MHz, MeOH-d4): δ ppm 1.57 (m, 4H), 1.99 (dd, J = 13.4, 7.1 Hz, IH), 2.26 (dd, J = 13.3, 9.1 Hz, IH), 2.40 (s, 3H), 3.02 (d, J = 1 1.6 Hz, IH), 3.18 (d, J = 1 1.6 Hz, IH), 3.48 (dq, J = 23.5, 7.1 , 6.6 Hz, 2H), 3.64 (dq, J = 1 1.4, 5.5 Hz, 2H), 3.99 (dd, J l bi
= 9.2, 7.0 Hz, IH), 5.73 (s, IH), 6.42 (d, J = 2.4 Hz, IH), 6.85 (q, J = 6.6 Hz, IH), 7.46 (t, J = 1.9 Hz, IH), 7.66 (t, J = 1.8 Hz, 3H)S 7.73 (dd, J = 8.3, 2,0 Hz, IH), 7.82 (d, J = 8.1 Hz, IH), 8.02 (d, J = 2.4 Hz, I H)
¾ NMR (400 MHz, MeOH-d4): δ ppm 1.28 (m, IH), 1.34 (s, 10H), 1.61 (t, J = 5.9 Hz, 4H), 2.06 (dd, J = 13.5, 7.3 Hz, IH), 2.39 (m, 7H), 3.14 (d, J = 1 1.6 Hz, IH), 3.25 (m, l bj IH), 3.55 (m, 2H), 3.68 (s, 2H), 4.18 (dd, J = 9.0, 7.3 Hz, IH), 6.42 (d, J = 2.3 Hz, IH), 6.78 (q, J = 6.5 Hz, IH), 7.28 (m, 2H), 7.45 (t, J = 1.7 Hz, IH), 7.60 (d, J = 1.8 Hz, IH), 7.75 (m, 2H), 7.98 (d, J = 2.3 Hz, IH)
Ή NMR (400 MHz, MeOH-d4): 8 ppm 1.28 (s, 2H), 1.58 (t, J = 5.5 Hz, 4H), 2.04 (dd, J = 13.3, 6,9 Hz, IH), 2.30 (dd, J = 13.3, 9.1 Hz, I H), 2.40 (s, 3H), 3.09 (d, J = 1 1.7 Hz, l bk H), 3,23 (d, J = 12.2 Hz, IH), 3.51 (m, 2H), 3.66 (dd, J = 13.9, 6.6 Hz, 2H), 4.05 (t, J = 8.2 Hz, IH), 4.62 (s, I H), 5.75 (s, I H), 6.42 (d, J = 2.4 Hz, IH), 6.82 (q, J = 6.5 Hz, IH), 7.43 (m, 2H), 7.63 (m, 2H), 7.75 (m, 3H), 8.00 (d, J = 2.3 Hz, IH)
Ή NMR (400 MHz, MeOH-d4): δ ppm 1.57 (t, J = 5,6 Hz, 4H), 2.00 (dd, J = 13.5, 7.0 Hz, IH), 2.26 (dd, J = 13.3, 9.1 Hz, IH), 2.40 (s, 3H), 3.03 (d, J = Π .6 Hz, I H), 3.18 (d, lbi J = 1 1.5 Hz, IH), 3.47 (ddd, J = 20.9, 14.0, 6.5 Hz, 2H), 3.64 (t, J = 7.4 Hz, 2H), 3.99 (dd, J = 9.1 , 7.1 Hz, IH), 5.74 (s, IH), 6.43 (d, J = 2,3 Hz, IH), 6.86 (q, J = 6.6 Hz, IH), 7.81 (m, 5H), 7.98 (d, J = 1.6 Hz, IH), 8.03 (d, J = 2.4 Hz, IH)
SH NMR (400 MHz, MeOH-d4): δ 1.54 (d, J=2.93 Hz, 4 H), 1.82 - 1.99 (m, 1 H), 2.09 - 2.24 (m, 1 H), 2.40 (s, 3 H), 2.79 - 2.93 (m, 1 H), 2.99 - 3.14 (m, 1 H), 3.37 - 3.55 (m, 2 H), 3.56 - 3.72 (m, 2 H), 3.82 (s, 4 H), 5,74 (s, 1 H), 6,41 (d, J=2.15 Hz, 1 H), 6.70 -
I bm
6.84 (m, 1 H), 6.99 (d, J=8.79 Hz, 2 H), 7.50 - 7.63 (m, 3 H), 7.64 - 7,71 (m, 1 H), 7.71 - 7.80 (m, 1 H), 7.95 (d, J=2.15 Hz, 1 H)
Ή NMR (400 MHz, MeOH-d4): 5 ppm 0.89 (m, IH), 1.28 (s, 2H), 1.42 (t, J = 7.0 Hz, 3H), 1.58 (t, J = 5.2 Hz, 4H), 2.05 (dd, J = 13.4, 7.0 Hz, IH), 2.31 (dd, J = 13.4, 9.0 Hz, lH), 2,39 (s, 3H), 3.1 1 (d, J = 1 1.8 Hz, IH), 3.24 (d, J = 1 1.7 Hz, 1H), 3.51 (m, 2H), l bn
3.67 (m, 2H), 4.13 (m, 3H), 4.63 (s, IH), 5.75 (s, IH), 6.41 (d, J = 2.3 Hz, IH), 6.78 (q, j = 6.6 Hz, I H), 7.15 (t, J = 8.6 Hz, I H), 7.45 (m, 2H), 7.60 (d, J = 1.8 Hz, IH), 7.73 (m, 2H), 7,97 (d, J = 2.4 Hz, IH) no 'H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 8.3 Hz, IH), 1.59 (t, J = 5.3 Hz, 4H), 2.05 (dd, J = 13.5, 7.0 Hz, IH), 2.32 (dd, J = 13.6, 9.2 Hz, lH), 2.39 (s, 3H), 3.12 (d, J = 11.6 Hz, IH), 3.25 (m, IH), 3.49 (ddd, J = 24.6, 12.8, 5.8 Hz, 2H), 3.66 (dq, J = lbo
12.7, 6.0 Hz, 2H), 4.09 (t, J == 8.1 Hz, IH), 5.76 (s, IH), 6.42 (d, J = 2.3 Hz, IH), 6.85 (q, J = 6.6 Hz, IH), 7.54 (m, 2H), 7.68 (d, J = 1.8 Hz, IH), 7.78 (m, 2H), 8.01 (d, J = 2.3 Hz, IH)
1H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 8.6 Hz, IH), 1.59 (d, J = 5.9 Hz, 4H), 2.05 (dd, J = 13.5, 7.3 Hz, IH), 2.39 (m, 7H), 3.13 (d, J = 11.6 Hz, IH), 3.24 (m, lbp 2H), 3.52 (dq, J = 25.3, 6.3 Hz, 2H), 3.68 (dd, J = 13.7, 5.9 Hz, 2H), 4.16 (m, IH), 6.42 (d, J = 2.3 Hz, IH), 6.82 (q, J = 6.5 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.51 (dd, J = 7.9, 2.0 Hz, IH), 7.63 (d, J = 1.9 Hz, IH), 7.73 (m, 3H), 7.98 (d, J = 2.4 Hz, IH)
Ή NMR (400 MHz, MeOH-d4): 8 ppm 1.29 (d, J = 8.0 Hz, IH), 1.59 (m, 4H), 2.05 (dd, J = 13.4, 7.0 Hz, IH), 2.38 (d, J = 13.7 Hz, 7H), 3.13 (d, J = 11.7 Hz, IH), 3.25 (d, J = lbq 11.6 Hz, IH), 3.53 (dt, J = 31.7, 10.3 Hz, 2H), 3.67 (dd, J = 13.5, 7.0 Hz, 2H), 4.15 (m, 1H), 4.89 (s, 17H), 6.42 (d, J = 2.4 Hz, IH), 6,82 (q, J = 6.6 Hz, lH), 7.32 (m, IH), 7.61 (m, 4H), 7.76 (m, 2H), 7.99 (d, J = 2.3 Hz, IH)
Ή NMR (400 MHz, MeOH-d4): δ ppm 0.90 (s, IH), 1.29 (m, 8H), 1.60 (d, J = 7.7 Hz, 4H), 2.02 (m, 2H), 2.39 (s, 4H), 3.14 (d, J = 1 1.6 Hz, IH), 3.25 (d, J = 11.4 Hz, IH), 3.51 (m, 2H), 3,66 (dd, J = 13.6, 6.6 Hz, 2H), 4.11 (dt, J = 21.0, 7.6 Hz, IH), 4.65 (h, J lbr
= 6.0 Hz, IH), 6.42 (d, J = 2.3 Hz, IH), 6.69 (dt, J = 10.9, 2.2 Hz, IH), 6.82 (q, J = 6.3 Hz, IH), 6.99 (m, 2H), 7.61 (d, J = 1.8 Hz, IH), 7.71 (m, IH), 7.78 (d, J = 8.1 Hz, IH), 7.99 (d, J = 2.3 Hz, IH)
'H MR (400 MHz, MeOH-d4): δ ppm 0.09 (s, IH), 0.90 (q, J = 8.4, 7.7 Hz, IH), 1.29 (d, J = 8,6 Hz, 3H), 1.59 (d, J = 5.7 Hz, 5H), 2.05 (dd, J = 13.5, 6.9 Hz, IH), 2.31 (dd, J = 13.6, 9.4 Hz, IH), 2.40 (s, 3H), 3,13 (d, J = 11.6 Hz, IH), 3.25 (m, IH), 3.61 (m, 5H), l bs
4.08 (m, IH), 5.74 (s, IH), 6.43 (d, J = 2.4 Hz, IH), 6.85 (q, J = 6.7 Hz, IH), 7.24 (dt, J = 8.5, 2.1 Hz, IH), 7.45 (dt, J = 9.6, 2.0 Hz, IH), 7.58 (t, J = 1.7 Hz, IH), 7.68 (d, J =
1.9 Hz, IH), 7.79 (m, 2H), 8.02 (d, J = 2.3 Hz, IH)
lH NMR (400 MHz, MeOH-d4): δ ppm 1.28 (d, J = 1.7 Hz, IH), 1.58 (t, J = 5.7 Hz, 4H), 2,03 (dd, J = 13.4, 7.0 Hz, IH), 2.29 (dd, J = 13.4, 9.2 Hz, IH), 2.40 (s, 3H), 3.07 l bt (d, J = 1 1.6 Hz, IH), 3.22 (d, J = 1 1.6 Hz, IH), 3.49 (m, 2H), 3.65 (dd, J = 13.0, 6.7 Hz, 2H), 4.04 (dd, J = 9.2, 7.0 Hz, IH), 5.73 (s, IH), 6.43 (d, J = 2.4 Hz, IH), 6.84 (q, J = 6.6 Hz, IH), 7.77 (m, 5H), 7.92 (dd, J = 8.4, 2.2 Hz, IH), 8.04 (dd, J = 14.2, 2.3 Hz, 2H)
Ή NMR (400 MHz, MeOH-d4): δ ppm 1.60 (d, J = 5.4 Hz, 411), 2.05 (dd, J = 13.5, 7.1 Hz, IH), 2.40 (s, 4H), 3.1 1 (d, J = 1 1.7 Hz, IH), 3.24 (d, J = 11.7 Hz, IH), 3.49 (ddt, J = lbu 21.1, 13.3, 6.0 Hz, 2H), 3.67 (dt, J = 12.9, 6.1 Hz, 2H), 4.07 (dd, J = 9.2, 7.1 Hz, IH), 5.74 (s, IH), 6.43 (d, J = 2.4 Hz, IH), 6.86 (q, J = 6.6 Hz, IH), 7.50 (m, IH), 7.80 (m, 5H), 8.04 (d, J = 2.4 Hz, IH)
!H NMR (400 MHz, MeOH-d4): δ ppm 1.35 (d, J = 6.0 Hz, 7H), 1.55 (d, J = 5.9 Hz, 4H), 1.98 (dd, J = 13.3, 7.0 Hz, IH), 2.25 (dd, J = 13.3, 9.1 Hz, IH), 2.39 (s, 2H), 3.01 (d, J = 11.5 Hz, IH), 3.17 (d, J = 11.6 Hz, IH), 3.47 (ddt, J = 20.8, 13.0, 6.0 Hz, 2H), lbv
3.64 (dd, J = 13.9, 6.3 Hz, 2H), 3.98 (dd, J = 9.2, 7.1 Hz, IH), 4.67 (p, J = 6.1 Hz, IH), 4.89 (s, 1 IH), 5.74 (s, IH), 6.41 (d, J = 2.4 Hz, IH), 6.79 (q, J = 6.6 Hz, IH), 7.13 (d, J = 8.7 Hz, IH), 7.55 (m, 2H), 7.71 (m, 4H), 7.98 (d, J = 2.4 Hz, IH)
¾ NMR (400 MHz, MeOH-d4): δ ppm 1.54 (t, J = 5.7 Hz, 4H), 1.95 (dd, J = 13.3, 7.0 lbw
Hz, IH), 2.22 (dd, J = 13.3, 9.0 Hz, IH), 2.41 (s, 3H), 2.95 (d, J = 11.5 Hz, IH), 3.13 (d, J = 1 1.4 Hz, IH), 3.47 (ddt, J = 19.9, 12.9, 5.9 Hz, 2H), 3.64 (dd, J = 13.3, 6.4 Hz, 2H), 3.94 (t, J = 8.1 Hz, IH), 4.91 (s, 1 OH), 5.77 (s, 1H), 6.43 (d, J = 2.3 Hz, IH), 6.83 (q, J = 6.6 Hz, IH), 7.49 (m, 2H), 7.83 (m, 7H), 8.01 (d, J = 2.4 Hz, IH), 8.13 (d, J = 1.9 Hz, IH)
Ή NMR (400 MHz, MeOH-d4): δ ppm 1.59 (m, 4H), 2,05 (dd, J = 13.5, 7.2 Hz, IH), 2.39 (s, 4H), 3.12 (d, J = 1 1.7 Hz, IH), 3.24 (d, J - 11.8 Hz, IH), 3.51 (m, 2H), 3.67 lbx (dd, J = 13.7, 6.2 Hz, 2H), 4.13 (dd, J = 9.1, 7.2 Hz, IH), 5, 19 (s, 2H), 6,41 (d, J = 2,3 Hz, IH), 6.79 (q, J = 6.5 Hz, IH), 7.21 (t, J = 8.6 Hz, IH), 7.42 (m, 7H), 7.60 (d, J = 1.8 Hz, IH), 7.72 (m, 2H), 7.97 (d, J = 2.3 Hz, IH)
'H NMR (400 MHz, MeOH-d4): 8 ppm 1.33 (dd, J = 6.1, 1.6 Hz, 6H), 1.58 (t, J = 5.2 Hz, 4H), 2.04 (dd, J = 13.5, 7.1 Hz, IH), 2.22 (s, 3H), 2.35 (m, 4H), 3.10 (d, J = 11.8 Hz, IH), 3.23 (d, J = 11.8 Hz, IH), 3.49 (ddt, J = 20.8, 13.6, 5,9 Hz, 2H), 3.66 (dd, J = lby
13.6, 6.9 Hz, 2H), 4.07 (dd, J = 9.2, 7.1 Hz, IH), 4.63 (p, J = 6.1 Hz, IH), 5.76 (s, IH), 6.41 (d, J = 2.4 Hz, IH), 6.75 (q, J = 6.7 Hz, IH), 6.97 (d, J = 8.2 Hz, IH), 7.45 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 1.8 Hz, IH), 7.71 (m, 2H), 7.96 (d5 J = 2.3 Hz, IH)
Ή NMR (400 MHz, MeOH-d4): δ ppm 1.06 (t, J = 7.4 Hz, 3H), 1.29 (m, H), 1.58 (d, J = 5,9 Hz, 4H), 1.83 (h, J = 7.1 Hz, 2H), 2.02 (dd, J = 13.4, 6.9 Hz, IH), 2.29 (dd, J = 13.3, 9.1 Hz, IH), 2.39 (s, 3H), 3,08 (d, J = 1 1.6 Hz, IH), 3.21 (d, J - 11.5 Hz, IH), lbz 3.48 (ddd, J = 2 .8, 12.6, 5.8 Hz, 2H), 3.65 (dd, J = 13.6, 7.3 Hz, 211), 4.04 (q, J = 7.1, 6.4 Hz, 3H), 4.97 (s, IH), 5.75 (s, IH), 6.41 (d, J = 2.3 Hz, IH), 6.78 (q, J = 6.5 Hz, IH), 7.14 (t, J = 8.6 Hz, IH), 7.44 (m, 2H), 7.59 (d, J = 1.9 Hz, IH), 7.72 (m, 2H), 7.98 (d, J = 2.3 Hz, IH)
Ή NMR (400 MHz, MeOH-d4): δ ppm 0.99 (t, J = 7.4 Hz, 3H), 1.53 (m, 6H), 1.79 (dq, J = 8.6, 6.5 Hz, 2H), 1.93 (dd, J = 13.2, 7.0 Hz, IH), 2.20 (dd, J = 13.3, 9.1 Hz, IH), 2.39 (s, 3H), 2,91 (d, J = 11,4 Hz, IH), 3.1 1 (d, J = 11.4 Hz, IH), 3.47 (ddt, J = 20.0, lea 13.0, 5.9 Hz, 2H), 3.64 (dd, J = 13.8, 5.7 Hz, 2H), 3.88 (t, J = 8.0 Hz, IH), 4.07 (t, J = 6.4 Hz, 2H), 5.75 (s, IH), 6.41 (d, J = 2.4 Hz, IH), 6.78 (q, J = 6.7 Hz, IH), 7.14 (t, J = 8.6 Hz, IH), 7.43 (m, 2H), 7.59 (d, J = 1.9 Hz, IH), 7.71 (m, 2H), 7.98 (d, J = 2.4 Hz, IH)
'H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (s, IH), 1.28 (s, IH), 1.62 (d, J = 6.2 Hz, 8H), 2.06 (dd, J = 13.3, 7.3 Hz, 2H), 2.41 (s, 8H), 2.65 (s, 5H), 3.15 (d, J = 12.0 Hz, leb 2H), 3.25 (m, 2H), 3.52 (s, 3H), 3.58 (s, 2H), 3.70 (d, J = 13.3 Hz, 4H), 4.21 (t, J = 8.4 Hz, 2H), 5.89 (s, IH), 6.00 (m, IH), 6.44 (d, J = 2.3 Hz, 2H), 6.89 (q, J = 6.4 Hz, 2H), 7.80 (m, 10H), 8.04 (d, J = 2.3 Hz, 2H), 8.12 (t, J = 7.9 Hz, 2H)
'H NMR (400 MHz, MeOH-d4): 8 ppm 1.29 (d, J = 6.2 Hz, IH), 1.57 (m, 4H), 1.99 (dd, J = 13.4, 7.0 Hz, J H), 2.25 (dd, J = 13.4, 9.1 Hz, IH), 2.40 (s, 3H), 3.01 (d, J = 11.6 Hz, IH), 3.15 (m, 4H), 3.32 (s, IH), 3.48 (ddt, J = 20.3, 12,8, 5.9 Hz, 2H), 3.65 (dd, J - lec
13.9, 7.0 Hz, 2H), 3.97 (dd, J = 9.1, 7.0 Hz, IH), 4.89 (m, 2H), 5.75 (s, IH), 6,44 (d, J =
2.4 Hz, IH), 6.85 (q, J = 6.6 Hz, IH), 7.75 (d, J = 1.7 Hz, IH), 7.84 (m, 2H), 7.94 (d, J =
8.5 Hz, 2H), 8.03 (m, 3H)
¾ NMR (400 MHz, MeOH-d4): δ ppm 1.05 (t, J = 7.4 Hz, 3H), 1.51 (q, J = 6.5, 5.7 Hz, 4H), 1.80 (h, J = 6.7, 6.1 Hz, 3H), 1.89 (d, J = 1.5 Hz, IH), 2.07 (dd, J = 12.7, 9.2 Hz, IH), 2.39 (s, 3H), 2.67 (d, J = 11.2 Hz, IH), 2.94 (t, J = 1 1.8 Hz, IH), 3.40 (m, 3H), led
3.64 (m, 3H), 3.96 (t, J = 6.4 Hz, 2H), 4.89 (m, IH), 5.75 (s, IH), 6.41 (d, J = 2.3 Hz, IH), 6.75 (m, IH), 6.99 (m, 2H), 7.59 (dd, J = 9.0, 2.0 Hz, 3H), 7.71 (m, 2H), 7.97 (d, J = 2.4 Hz, IH) !H NMR (400 MHz, MeOH-d4): 5 ppm 1 ,30 (d, J = 16.9 Hz, 4H), 1.57 (s, 5H), 2.02 (m, IH), 2.27 (dd, J = 13.3, 8.8 Hz, IH), 2.40 (s, 3H), 2.60 (m, 6H), 3.06 (d, J = 1 1.4 Hz, IH), 3.20 (d, J = 1 1.3 Hz, IH), 3.34 (s, IH), 3.48 (s, 3H), 3.56 (t, J = 6.7 Hz, 2H), 3.70
Ice
(m, 7H), 4.02 (s, IH), 4.98 (d, J = 6.2 Hz, IH), 5.76 (s, IH), 6.43 (d, J = 2.3 Hz, IH), 6.82 (q, J = 6.5 Hz, IH), 7.71 (s, IH), 7.80 (m, 4H), 7.93 (d, J = 8.0 Hz, 2H), 8.01 (d, J = 2,3 Hz, IH)
Ή NMR (400 MHz, MeOH-d4): δ ppm 0.90 (t, J = 6.4 Hz, IH), 1.30 (dd, J = 12.6, 4.9 Hz, 6H), 1.55 (m, 5H), 1.93 (dd, J = 13.2, 7.0 Hz, IH), 2.19 (qd, J = 9.4, 3.3 Hz, IH), 2.40 (s, 3H), 2,92 (d, J = 11.4 Hz, IH), 3.11 (d, J = 11.3 Hz, IH), 3,48 (m, 2H), 3,65 lcf
(dd, J = 13.7, 6.3 Hz, 2H), 3.88 (dd, J = 8.9, 7.2 Hz, IH), 4.87 (d, J = 12.3 Hz, IH), 4.97 (d, J - 12.9 Hz, 2H), 5.75 (s, IH), 6.43 (d, J = 2.3 Hz, IH), 6.83 (q, J = 6.7 Hz, IH), 7.73 (s, IH), 7.84 (m, 4H), 8.00 (m, 3H)
'I-I NMR (400 MHz, MeOH-d4): δ ppm 1.29 (s, IH), 1.58 (d, J = 5.9 Hz, 4H), 2.03 (dd, J = 13.4, 6.9 Hz, IH), 2.30 (dd, J = 13.3, 9.2 Hz, IH), 2.40 (s, 3H), 3,1 1 (d, J = 1 1.7 Hz, leg IH), 3,23 (d, J = 1 1.5 Hz, IH), 3.48 (ddd, J = 28.3, 12.4, 5.7 Hz, 2H), 3.65 (dd, J = 13.7, 7.2 Hz, 2H), 4.07 (m, IH), 5.76 (s, IH), 6.43 (d, J = 2.3 Hz, IH), 6.82 (q, J = 6.5 Hz, IH), 7.70 (d, J = 1 ,7 Hz, IH), 7.79 (dt, J - 13.1, 8.1 Hz, 4H), 7.99 (m, 3H)
JH NMR (400 MHz, MeOH-d4): 6 ppm 1.29 (d, J = 3.6 Hz, IH), 1.63 (q, J = 5.8 Hz, 5H), 2.07 (dd, J = 13.5, 7.5 Hz, IH), 2.37 (dd, J = 13.5, 9.0 Hz, IH), 3,04 (s, 3H), 3.15 lch
(d, J = 24.6 Hz, 6H), 3.27 (m, IH), 3.52 (dt, J = 24.6, 8.3 Hz, 2H), 3.65 (m, 2H), 4.23 (t, J = 8.1 Hz, IH), 6.66 (q, J = 7.0 Hz, IH), 7.51 (d, J = 8.1 Hz, 2H), 7.68 (m, 6H) lH NMR (400 MHz, MeOH-d4): δ ppm 1.58 (d, J = 5,6 Hz, 4H), 2.03 (dd, J = 13.3, 7.1 Hz, IH), 2.30 (dd, J = 13.4, 9.2 Hz, IH), 2.39 (s, 3H), 3.09 (d, J = 11.7 Hz, IH), 3.22 (d, J = 11.7 Hz, IH), 3.49 (ddd, J = 21.1 , 12.5, 5.6 Hz, 2H), 3.66 (dd, J = 13.7, 6.7 Hz, 2H), lci
3.90 (s, 3H), 4.06 (dd, J = 9.2, 7.1 Hz, IH), 5.76 (s, I H), 6.41 (d, J = 2.3 Hz, I H), 6.78 (q, J = 6.6 Hz, IH), 7.17 (t, J = 8.9 Hz, IH), 7.46 (m, 2H), 7.60 (d, J = 1.8 Hz, IH), 7.73 (m, 2H), 7.98 (d, J = 2.3 Hz, IH)
Ή NMR (400 MHz, MeOH-d4): δ ppm 1 ,30 (d, J = 17.0 Hz, IH), 1.57 (d, J - 5.5 Hz, 4H), 2.01 (dd, J = 13.2, 7.0 Hz, IH), 2.28 (dd, J = 13.3, 9.0 Hz, IH), 2.40 (s, 3H), 2.79 (s, 2H), 2.91 (s, 2H), 3.07 (d, J = 12.1 Hz, IH), 3,20 (d, J = 11.4 Hz, IH), 3.49 (m, 4H), lcj 3.65 (dd, J = 13.5, 6.9 Hz, 2H), 3.74 (s, 2H), 4.02 (t, J = 8.1 Hz, IH), 4.99 (s, IH), 5.76 (s, IH), 6.43 (d, J = 2.4 Hz, IH), 6.82 (q, J = 6.6 Hz, IH), 7.52 (d, J = 7.9 Hz, 2H), 7.76 (m, 5H), 8.01 (d, J = 2.4 Hz, IH)
H NMR (400 MHz, MeOH-d4): δ ppm 1.30 (d, J = 11.1 Hz, IH), 1.51 (q, J = 6.8, 6.0 Hz, 4H), 1.78 (dd, J = 13.0, 7.0 Hz, IH), 1.89 (s, 2H), 2.07 (dd, J = 13,1, 9.1 Hz, IH), 2.40 (s, 3H), 2.68 (d, J = 1 1.1 Hz, IH), 2.95 (d, J = 1 1.1 Hz, IH), 3.03 (s, 3H), 3.11 (s, lck
3H), 3.22 (s, 2H), 3.45 (m, 3H), 3.63 (q, J = 7.9, 7.5 Hz, 3H), 5.75 (s, IH), 6.43 (d, J = 2.4 Hz, IH), 6.82 (q, J = 6.6 Hz, IH), 7.53 (d, J = 7,9 Hz, 2H), 7.70 (m, IH), 7.80 (m, 4H), 8.01 (d, J = 2.5 Hz, IH)
Ή NMR (400 MHz, MeOH-d4): δ ppm 1.04 (d, J = 6.7 Hz, 6H), 1.29 (m, IH), 1.60 (d, J = 6,0 Hz, 5H), 2,05 (ddd, J = 13.7, 7.0, 3.9 Hz, 2H), 2.36 (m, 4H), 3.13 (d, J = 1 1.9 Hz, IH), 3.24 (d, J = 1 1.6 Hz, IH), 3.51 (ddd, J = 25,5, 14.3, 7.1 Hz, 2H), 3.69 (d, J = lci
13.8 Hz, 3H), 3.77 (d, J = 6.4 Hz, 2H), 4.14 (t, J = 8.3 Hz, IH), 4.93 (s, 8H), 6,41 (d, J = 2.3 Hz, IH), 6.77 (q, J = 6.6 Hz, IH), 6.99 (m, 2H), 7.60 (m, 3H), 7.72 (m, 2H), 7.96 (d, J = 2.3 Hz, IH)
1cm Ή NMR (400 MHz, MeOH-d4): δ 1.14 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.3 Hz, 3H), 1.55 (q, J = 4.8 Hz, 4H), 1.90 (m, I H), 2.18 (dd, J = 13.2, 9.0 Hz, 1H), 2.40 (s, 3H), 2.87 (d, J = 1 1 .4 Hz, IH), 3.09 (d, J = 11.3 Hz, IH), 3.30 (m, 4H), 3.54 (dddd, J = 37.2, 30.6, 15.1 , 5.9 Hz, 61-1), 3.84 (dd, J = 9.0, 6.9 Hz, IH), 5.76 (s, IH), 6.42 (d, J = 2.3 Hz, IH), 6.83 (q, J = 6.6 Hz, IH), 7.48 (m, 2H), 7.70 (d, J = 1.6 Hz, IH), 7.80 (m, 4H), 8.01 (d, J = 2.3 Hz, IH)
'H NMR (400 MHz, MeOH-d4): δ ppm 0.84 (s, 3H), 1.06 (s, 10H), 1.30 (m, I H), 1.56 (t, J = 5.4 Hz, 4H), 2.00 (dd, J = 13.4, 6.8 Hz, IH), 2.27 (dd, J = 13.2, 9.0 Hz, IH), 2.41 (s, 3H), 3.04 (d, J = 1 1.5 Hz, IH), 3.19 (d, J = 1 1.4 Hz, IH), 3.48 (ddt, J = 20.4, 13.0, lcn
5.9 Hz, 2H), 3.65 (s, 4H), 4.03 (t, J = 8.1 Hz, I H), 5.77 (s, IH), 6.43 (d, J = 2.2 Hz, IH), 6.79 (q, J = 6.6 Hz, IH), 6.98 (d, J = 8.4 Hz, 2H), 7.60 (m, 4H), 7,75 (d, J = 8.2 Hz, IH), 7.97 (d, J = 2.3 Hz, IH)
'H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (d, J = 5.8 Hz, IH), 1.55 (t, J = 5.7 Hz, 4H), 1.98 (m, 3H), 2.25 (dd, J = 13.3, 9.2 Hz, IH), 2.39 (s, 3H), 2.80 (t, J = 6.5 Hz, 2H), 3.02 (d, J = 1 1.6 Hz, IH), 3.17 (d, J = 11.6 Hz, IH), 3.47 (ddt, J = 20.5, 13.0, 5.9 Hz, lco 2H), 3.64 (dt, J = 13.8, 5.9 Hz, 2H), 4.00 (dd, J = 9.2, 7.1 Hz, IH), 4.16 (m, 2H), 5.75 (s, IH), 6.40 (d, J = 2.3 Hz, IH), 6.76 (m, 2H), 7.33 (d, J = 6.5 Hz, 2H), 7.54 (d, J = 1.8 Hz, IH), 7.63 (dd, J = 8.3, 1.9 Hz, IH), 7.71 (d, J = 8.3 Hz, IH), 7.95 (d, J = 2.4 Hz, IH)
Ή NMR (400 MHz, MeOH-d4): δ ppm 1.59 (t, J = 5.3 Hz, 4H), 2.05 (dd, J = 13.5, 7.1 Hz, IH), 2.31 (dd, J = 13.4, 9.3 Hz, IH), 2.42 (s, 3H), 3. 1 1 (d, J = 1 1.7 Hz, IH), 3.24 (d, J = 1 1.7 Hz, IH), 3.51 (m, 2H), 3.67 (s, 2H), 4.07 (dd, J = 9.3, 7.1 Hz, IH), 4.89 (s, IH), lcp
5.78 (s, IH), 5.99 (m, IH), 6.46 (d, J = 2.3 Hz, IH), 6.89 (q, J = 6.5 Hz, IH), 7.91 (m, 2H), 8.00 (dd, J = 8.3, 2.0 Hz, IH), 8.07 (d, J = 2.4 Hz, IH), 8.34 (m, 3H), 8.55 (d, J = 8.9 Hz, IH), 9.33 (d, J = 5.9 Hz, IH)
!H NMR (400 MHz, MeOH-d4): δ ppm 7.97 (s, I H), 7.77 (s, 2H), 7.67 (d, J = 15.8 Hz, 2H), 7.51 (s, I H), 7.26 (d, J = 7.8 Hz, IH), 6.42 (s, IH), 4.69 (s, 2H), 4.14 (s, IH), 3.68
Icq
(s, 2H), 3.51 (s, 3H), 3.23 (s, IH), 3.13 (d, J = 1 1.6 Hz, IH), 2.38 (d, J = 14.0 Hz, 6H), 2.05 (s, IH), 1.60 (s, 4H), 1.29 (s, 3H)
lU NMR (400 MHz, MeOH-d4): δ ppm 7.97 (s, 2H), 7.74 (q, J = 8.3 Hz, 4H), 7.62 (s, 2H), 7.46 (d, J = 7.4 Hz, 5H), 6.78 (q, J = 6.7 Hz, 2H), 6.41 (s, 2H), 5.75 (s, 2H), 4.65 (s, 3H), 4.07 (t, J = 8.1 Hz, 2H), 3,64 (s, 4H), 3.52 (d, J = 6.9 Hz, IH), 3.46 (d, J = 16.2 l ci- Hz, 4H), 3.22 (d, J = 1 1.8 Hz, 2H), 3.10 (d, J = 1 1.8 Hz, 2H), 2.38 (d, J = 7.9 Hz, 10H), 2.29 (s, IH), 2.03 (dd, J = 13.4, 7.0 Hz, 211), 1.58 (d, J = 5.6 Hz, 7H), 1.30 (d, J = 13.4 Hz, 5H)
Ή NMR (400 MHz, MeOH-d4); δ ppm 8.43 (d, J - 2.5 Hz, IH), 7.99 (q, J = 3.3 Hz, 2H), 7.79 (d, J = 8.3 Hz, IH), 7.72 (d, J = 8.1 Hz, IH), 7.63 (s, IH), 6.83 (dd, J = 20.4, 7.6 Hz, 2H), 6.42 (d, J = 2.3 Hz, IH), 5.74 (s, IH), 4.35 (q, J = 7.0 Hz, 2H), 3.96 (d, J = lcs
8.9 Hz, IH), 3.64 (s, 3H), 3.48 (dd, J = 25.9, 1 1.9 Hz, 2H), 3.15 (d, J = 1 1 ,7 Hz, IH), 2.99 (d, J = 1 1.4 Hz, IH), 2.39 (s, 3H)} 2.24 (s, IH), 2.02 - 1 ,94 (m, IH), 1.56 (s, 4H), 1.38 (t, J = 7.1 Hz, 3H), 1.28 (s, IH).
Example lcp: (Si-S-i -amino^-tiRi-l-iS'^'-dimethyl-S-iS-itrifluorometh li-lH- razol-l- yl)-[l,l'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimi(lin-4-yI)-2,8-diazaspiro[4.5Jdecane-3- carboxylic acid
Figure imgf000116_0001
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-2,2,2-trifluoi -l-(3-(3- methyl- 1 H-pyrazol-1 -yl)-[l , r-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid (Example lu) starting with (S)-8-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH- pyrazol- 1 -yl)phenyl)-2;2,2-trifluoroethoxy)pyrimidin-4-yl)-2J8-diazaspiro [4.5] decane-3 - carboxylic acid (Example lOd).
'H NMR (400 MHz, MeOH-d4): δ ppm 1.57 (br. s., 4 H) 1.91 - 2.01 (m, 1 H) 2.18 - 2.27 (m, 1 H) 2.33 (d, J=l 1.71 Hz, 6 H) 2.88 - 3.00 (m5 1 H) 3.08 - 3.19 (m, 1 H) 3.38 - 3.56 (m, 2 H) 3.58 - 3.75 (ra, 2 H) 3.85 - 3.98 (m, 1 H) 5.65 (s, 1 H) 6.55 - 6.70 (m, 1 H) 6.92 - 7.04 (m, 1 H) 7.19 - 7.28 (m, 1 H) 7.38 - 7.46 (m, 1 H) 7.46 - 7.53 (m, 1 H) 7.72 (s, 1 H) 7.83 (s, 2 H) 8.22 - 8.35 (m, 1 H)LCMS (MH+): 690.
Example 2: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(2-(3-methyi-lH-pyrazol-l-yl)-4- (piperidiii-4-yl)phenyl)c hoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid
Figure imgf000116_0002
Step l A solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoiO-l-(2-(3-metliyl- lH-pyrazol-l-yl)-4-(l,2,3,6-tetrahydiOpyiidin-4-yl)phenyl)ethoxy)pyi'imidin-4-yl)-2J8- diazaspiro[4.5]decane-2,3-dicarboxy]ate (Example If) (150 mg, 0.15 mmol) in MeOH (5 mL) was hydrogenated in an H-Cube apparatus using a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 mL/min at RT. The resulting eluent was concentrated in vacuo and The product was purified by column chromatography using an Isco Gold reversed phase silica cartridge (100% CH2CI2 to 90:9: 1 CH2Cl2:MeOH:conc. NH4OH) to provide (S)-2-benzyl 3-ethyl 8-(2-amino-6- ((R)-2)2)2-trifluoiO-l-(2~(3-methyl-lH-pyrazol-l -yl)-4-(l,2}336-tetrahydiOpyridin-4- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate.
Step 2: Hydrolysis of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-l -(2-(3-methyl-lH- pyrazol-l-yl)-4-(l ,2)3,6-tetrahydiOpyi'idin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-2,3-dicarboxylate using the LiOH general method provided the title compound as an off-white solid.
'H NMR (400 MHz, MeOH-d4): δ ppm 1.49 - 1.69 (m, 4 H) 2.00 - 2.18 (m, 3 H) 2.21 - 2.35 (m, 1 H) 2.38 (s, 3 H) 2.92 - 3.05 (m, 1 H) 3.08 (d, J=0.44 Hz, 2 H) 3.10 - 3.18 (m, 2 H) 3.25 (d, J=l 1.71 Hz, 1 H) 3.38 - 3.72 (m, 7 H) 4.09 (t, J=7.88 Hz, 1 H) 5.69 (s, 1 H) 6.41 (d} J=2.29 Hz, 1 H) 6.74 (q, J=6.80 Hz, 1 H) 7.34 (d, J=1.12 Hz, 1 H) 7.43 (d, J=8.15 Hz, 1 H) 7.71 (d, J=8.44 Hz, 1 H) 7.91 (d, J=2.20 Hz, 1 H). LCMS (MH+): 613.
Example 3a: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(2-(3-mcthyl-lH-pyrazol-l-yl)-4-(l- (methyIsulfonyI)piperidin-4-yI)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]dccane-3- carboxylic acid
Figure imgf000117_0001
Step 1: To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2;2,2-trifluoi -l-(2-(3-methyl- lH-pyrazol-l -yl)-4-(l ,2,3,6-tetrahydropyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-2,3-dicarboxylate (320 mg, 0.413 mmol) in CH2CI2 (5.0 mL) was added methanesulfonyl chloride (47 mg, 0.41 mmol) and triethylamine (94 mg, 0.83 mmol), and the reaction was stirred for 1.5 h at RT and then concentrated in vacuo. The product was purified by column chromatography using an Isco Gold reversed phase silica cartridge (100% CH2CI2 to 90:9: 1 CH2Cl2:MeOH:conc. NH4OH) to provide (S)-2-benzyi 3-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro- 1 -(2-(3-methyl-lH-pyrazol- 1 -yl)-4-(l -(methylsulfonyl)- 1 ,2J3,6-tetrahydropyridin-4- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4,5]decane-2;3-dicarboxylate as an off-white solid.
Step 2: A solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2;2,2-tnfluoiO-l-(2-(3-methyl-lH- pyrazol-l-yl)-4-(l-(methylsulfonyl)-l ,2,3,6-tetrahydi pyiidin-4-yl)phenyl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (290 mg, 0.340 mmol, Step 1) in MeOH (10 mL) was hydrogenated in an H-Cube apparatus using a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 mL/min at RT. The resulting eluent was concentrated in vacuo and The product was purified by column chromatography using an Isco Gold reversed phase silica cartridge (100% CH2C12 to 90:9:1 CH2Cl2:MeOH:conc. NH4OH) to provide (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro- 1 -(2- (3 -methyl- lH-pyrazol- 1 -yl)-4-(l -(methylsulfonyl)piperidin-4- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate,
Step 3: Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoi -l -(2-(3-methyl-lH-pyrazol-l - yl)-4-(l-(methyIsulfonyl)piperidin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4,5]decane-3-carboxylate using the LiOH general method provided the title compound as an off-white solid. lH N R (400 MHz, MeOH-d4): δ ppm 1.53 - 1.65 (m, 4 H) 1.80 (qd, J=12.57, 3.98 Hz, 2 H) 1.94 - 2.02 (m, 2 H) 2.02 - 2.12 (m, 1 H) 2.31 (dd, J=13.42, 9.27 Hz, 1 H) 2.38 (s, 3 H) 2.67 - 2.94 (m, 3 H) 2.86 (s, 3 II) 3.07 - 3.28 (m, 2 H) 3.37 - 3,74 (m, 4 H) 3.78 - 3.92 (m, 2 H) 4.08 (dd, J=9.1 , 7.20 Hz, 1 H) 5.71 (s, 1 H) 6.39 (d, J=2.29 Hz, 1 H) 6.64 - 6.82 (m, 1 H) 7.31 (d, J=1.71 Hz, 1 H) 7.42 (dd, J=8.25, 1.76 Hz, 1 H) 7.67 (d, J=8.10 Hz, 1 H) 7.89 (d, J=2.29 Hz, 1 H). LCMS (MH+): 693.
Using the generic scheme below, the following examples of Table 2a can be prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoi -l-(2-(3-methyl-lH-pyrazol-l-yl)-4-(l- (methylsulfonyl)pipeiidin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)~2,8-diazaspiro[4.5]decane-3- carboxylic acid (Example 3 a).
Figure imgf000119_0001
Figure imgf000119_0002
Ex. CAS Name LCMS (MH+) No.
3b (S)-8-(6-((R)-l-(4~(l-acetylpiperidin-4-yl)-2-(3- 656.7
methyl- IH-pyrazol- 1 -yl)phenyl)-2,2,2- trifluoroethoxy)-2-aminopyiimidin-4-yl)-2,8- diazaspii [4.5]decane-3-cai'boxyIic acid
3c (S)-8-(2-amino-6-((R)-2,2,2-tiifliioiO- 1 -(2-(3-methyl- 615.6
lH-pyrazol- 1 -yl)-4-(tetrahydro-2H-pyran-4- y l)phenyl)ethoxy)pyrim id i n-4 -yl) -2 , 8 - diazaspiro [4.5] decane-3 ~c arb oxylic acid
Tabic 2b.
NMR Data for Compounds of Table 2a Ex, 1H NMR
No.
3b 'H NMR (400 MHz, MeOH-d4): δ ppm 1.54 - 1.82 (m, 6 H) 1.86 - 1.99 (m, 2 H) 2.05 - 2.18 (m, 4 H) 2.36 - 2.38 (m, 3 H) 2.48 (dd, J=13.69, 8.86 Hz, 1 H) 2.66 - 2.81 (m, 1 H) 2.88 - 3.03 (m, 1 H) 3.19 - 3.27 (m, 1 H) 3.31 - 3.40 (m, 1 H) 3.60 - 3,95 (m, 4 H) 4.05 (d, J=13.08 Hz, 1 H) 4.55 (t, J=8.66 Hz, 1 H) 4.67 (d, J=13.13 Hz, 1 H) 6.39 (d, J=2.39 Hz, 1 H) 6.50 (br. s., 1 H) 6.79 - 6.87 (m, 1 H), 7.36 (s, 1 H) 7.47 (dd, J=8.22, 1.64 Hz, 1 H) 7.64 (d, J=8.30 Hz, 1 H) 7.86 (d, J=2.39 Hz, 1 H)
3c !H NMR (400 MHz, MeOH-d4): δ ppm 1 ,59 (d, J=5.08 Hz, 4 H) 1.72 - 1.89 (m, 4 H) 2.06 (dd, J=13.45, 7.15 Hz, 1 H) 2.32 (dd, J=13.45, 9.25 Hz, 1 H) 2.38 (s, 3 H) 2.82 - 2,95 (m, 1 H) 3.07 - 3.16 (m, 1 H) 3.25 (d, J=l 1.76 Hz, 1 H) 3.36 - 3.74 (m, 6 H) 4.03 (dt, J=l 1.16, 2.96 Hz, 2 H) 4.08 (dd, J=9.15, 7.20 Hz, 1 H) 5.71 (s, 1 H) 6.39 (d, J=2,29 Hz, 1 H) 6.72 (q, J=6.75 Hz, 1 H) 7.29 (d, J=l ,71 Hz, 1 H) 7.41 (dd, J=8.20, 1.76 Hz, 1 H) 7.67 (d, J=8.10 Hz, 1 H) 7.88 (d, J=2.34 Hz, 1 H)
Example 4: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3,-methoxy-4'-(methoxycarbonyI)-3-(3- methyHH-pyrazol-l-yl)-[l,l'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decan -3-carboxyIic acid
Figure imgf000120_0001
Step 1: To a solution of (S)-8-(2-amino-6-((R)-l -(4-bromo-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2)2-ti'ifluoiOethoxy)pyrimidin-4-yl)-2-((benzyloxy)caibonyl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid (product of Step 3, Example 10m) (135 mg, 0.18 mmol) in dioxane (2 mL) was added (3-methoxy-4-(methoxycarbonyl)phenyl)boronic acid (84 mg, 0,4 mmol) and CS2CO3 (48 mg, 0.16 mmol), The reaction was heated to 80 °C for 16 h, cooled to RT, and filtered, The solvent was removed in vacuo. Purification via normal phase silica gel chromatography (CHiCk/Heptane) provided (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1 -(3'- methoxy-4'-(methoxycarbonyl)-3-(3-methyl-lH-pyrazoi-l-yl)-[l, -biphenyl]-4- yl)ethoxy)pyrimidin-4-yI)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as an off-white solid. Step 2: N-CBZ Deprotection was accomplished via method B to yield (S)-8-(2-amino-6-((R)- 2,2,2-trifluoro- l-(3'-methoxy-4'-(methoxycarbonyl)-3-(3-methyl- 1 H-pyrazol-l -yi)-[l , 1 '- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as an off- white solid.
Ή NMR (400 MHz, MeOH-d4): δ ppm 1.66 (d, J=5.47 Hz, 4 H) 2.03 - 2.17 (m, 1 H) 2.42 (s, 4 H) 3.16 - 3.30 (m, 2 H) 3.47 - 3.81 (m, 4 H) 3.89 (s, 3 H) 3.97 (s, 3 H) 4.26 - 4.45 (m, 1 H) 6.40 - 6.52 (m, 1 H) 6.82 - 6.96 (m, 1 H) 7.30 - 7.37 (m, 1 H) 7.40 (s, 1 H) 7.76 (s, 1 H) 7.80 - 7.93 (m, 4 H) 7.99 - 8.09 (m, 1 H). LCMS: 696.7.
Example 5a: (S)-8-(2-amino-6-((R)-l-(3'-(ethoxycarbonyl)-3-(3-methyl-lH-pyrazol-l-yl)- [l, -biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]dccane-3- carboxylic acid
Figure imgf000121_0001
The title compound was made according to the procedures described for (S)-8-(2-amino-6-((R)- 2,2,2-trifluoro- 1 -(3,-methoxy-4'-(methoxycarbonyl)-3-(3-methyl- 1 H-pyrazol- 1 -yl)-[l , - biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4,5]decane-3-carboxylic acid (Example 4).
Ή NMR (400 MHz, MeOH-d4): δ ppm 1.42 (t, J=7.13 Hz, 3 H) 1.61 (br. s„ 4 H) 2.02 - 2.14 (in, 1 H) 2.28 - 2.40 (m, 1 H) 2.42 (s, 3 H) 3.06 - 3.19 (m, 1 H) 3.21 - 3.30 (m, 1 H) 3.40 - 3.60 (m, 2 H) 3.62 - 3.80 (m, 2 H) 4.01 - 4.19 (m, 1 H) 4.41 (d, J=7.22 Hz, 2 H) 5.76 (s, 1 H) 6.45 (d, J=2.34 Hz, 1 H) 6.79 - 6.92 (m, 1 H) 7.60 (s, 1 H) 7.70 (d, J=1.56 Hz, 1 H) 7.80 (d, J=1.56 Hz, 1 H) 7.84 (s, 1 H) 7.90 - 7.97 (m, 1 H) 8.02 (d, J=2.15 Hz, 1 H) 8.05 (s, 1 H) 8.31 (s, 1 H) 680.7. LCMS (MH+): 578.7. Example 5b: (S)-8-(2-amino-6-((R)-l-(4'-(ethoxycarbonyl)-3-(3-methyl-lH-pyrazol-l-yl)- [l,l'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yI)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
Figure imgf000122_0001
The title compound was made according to the procedures described for (S)-8-(2-amino-6-((R)- 2,2,2-trifluoro- 1 -(3'-methoxy-4'-(methoxycai'bonyl)-3-(3-methyl- 1 H-pyrazol- 1 -yi)-[l , 1 '- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2J8-diazaspii'o[4.5]decane-3-carboxylic acid (Example 4).
*H NMR (400 MHz, MeOH-d4): δ ppm0.88 (m, 4H), 1.30 (d, J = 17.4 Hz, 10H), 1.40 (t, J = 7.1 Hz, 4H), 1.59 (d, J = 5.8 Hz, 5H), 2.05 (dd, J = 13.5, 7.2 Hz, 1H), 2.35 (m, 5H), 3.11 (d, J = 11.7 Hz, 1H), 3.24 (d, J = 11.7 Hz, 1H), 3.49 (ddd, J = 28.1, 12.7, 5.7 Hz, 2H), 3.66 (dd, J = 13.2, 7.3 Hz, 3H), 4.07 (t, J = 8.1 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 4.82 (d, J = 9.7 Hz, 1H), 4.91 (s, 2H), 5.75 (s, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.83 (q, J = 6.5 Hz, 1H), 7.72 (d, J = 1.6 Hz, 1H), 7.81 (m, 4H), 8.00 (d, J = 2.4 Hz, 1H), 8.10 (m, 2H). LCMS (MH+): 681.
Example 6; (S)-8-(2-amino-6-((R)-l-(4-(3-carboxypropyl)-2-(3-mcthyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000122_0002
Step 1: To a solution of 9-borabicyclo[3.3.1]nonane (2.0 mL, 0.5 M in THF, 1.0 mmol) was added methyl but-3-enoate (100 μΐ,, 1.0 mmol) and stirred at RT for 2 h to prepare the 9- BBN/butane solution. Step 2: To a solution of (S)-8-(2-amino-6-(( )-l-(4-bromo-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2)8-diazaspiro
[4.5]decane-3-carboxylic acid (product of Step 3, Example 10m) (250 mg, 0.32 mmol) in THF (2 mL) was added sequentially PdChidp fjCH^Ch (8 mg, 0.01 mmol), NaOEt (66 mg, 1 mmol) and the prepared 9-BBN/butene solution from Step 1. The reaction was heated to 65 °C for 2 h, then cooled to RT. The reaction was extracted with EtOAc, brine and dried over Na2S04 and concentrated in vacuo. The product was purified by column chromatography using an Isco Gold reversed phase silica cartridge (100% CH2C12 to 90:9:1 CHaCbiMeOHxonc. NH4OH) to provide (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2>2,2-trifluoro-l-(4-(4-methoxy-4-oxobutyl)-2-(3- methyl-lH-pyrazol-l-yl)phenyl)ethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3- dicarboxylate as an off-white solid.
Step 3: N-CBZ Deprotection was accomplished via method B to provide (S)-ethyl 8-(2-amino-6- ((R)-2,2,2-trifluoi - 1 -(4-(4-methoxy-4-oxobutyl)-2-(3-methyl- 1 H-pyrazol - 1 -yi)phenyl) ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as an off-white solid.
Step 4: Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoiO-l-(4-(4-methoxy-4-oxobutyl)- 2-(3-methyI-l H-pyrazol- l-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate was carried out using the LiOH general method providing the title compound as an off-white solid.
!H NMR (400 MHz, DMSO-d6): 5 ppm 1.40 - 1.61 (m, 4 H) 1 ,76 - 1.93 (m, 3 H) 2.24 (t, J=7.35 Hz, 2 H) 2.27 - 2.37 (m, 4 H) 2.58 - 2.74 (m, 2 H) 3.10 (br. s., 2 H) 3.53 (br. s„ 4 H) 4.42 (br. s., 1 H) 5.71 (br. s., 1 H) 6.00 (br. s., 2 H) 6.38 (d, J=2.20 Hz, 1 H) 7.00 (q, J=6.87 Hz, 1 H) 7.29 (d, J=1.51 Hz, 1 H) 7.32 - 7.41 (m, 1 H) 7.60 (s, 1 H) 8.05 (d, J=2.29 Hz, 1 H) 8.94 (br. s„ 1 H) 10.20 (br. s, 1 H) 12.14 (br. s., 1 H). LCMS (MH+): 618.6. Example 7: (S)-8-(2-amino-6-((R)-l-(4-(2-carboxyethyl)-2-(3-methyl-lH-pyrazoI-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4,5]decane-3-carboxyIic acid
Figure imgf000124_0001
The title compoimd was made as described for (S)-8-(2-amino-6-((R)-l-(4-(3-carboxypropyl)-2- (3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2-tnfluoi ethoxy)pyrimidin-4-yl)-2,8- diazaspiiO[4.5]decane-3-carboxylic acid (Example 6).
Ή NMR (400 MHz, MeOH-d4): δ ppm 1.56 (t, J=5.54 Hz, 4 H) 1.97 (s, 2 H) 2.04 (dd, 1=13.30, 7.10 Hz, 1 H) 2.29 (dd, J=13.67, 9.18 Hz, 1 H) 2.35 (s, 3 H) 2.59 - 2.68 (m, 2 H) 2.97 (t, J=7.49 Hz, 2 H) 3.06 - 3.13 (m, 1 H) 3.23 (d, J=l 1.86 Hz, 1 H) 3.39 - 3.55 (m, 2 H) 3.57 - 3.75 (ra, 2 H) 4.06 (dd, J=9.05, 7.30 Hz, 1 H) 5.72 (s, 1 H) 6.36 (d, J=2.29 Hz, 1 H) 6.71 (q, J-6.61 Hz, 1 H) 7.28 (d, J=1.61 Hz, 1 H) 7.37 (dd, J=8.20, 1.46 Hz, 1 H) 7.62 (d, 1=8.10 Hz, 1 H) 7.83 (d, J=2.25 Hz, 1 H). IXMS (MH+): 604.
Example 9: (S)-8-(2-amnio-6-((R)-l-(4-(3-ethoxy-3-oxopropyl)-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluorocthoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000124_0002
Step I : To a solution of (S)-8-(2-amino-6-((R)- 1 -(4-bromo-2-(3-methyI- 1 H-pyrazol- 1 - yl)phenyi)-2,2,2-trifluoi ethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid (product of Step 3, Example 10m) (240 mg, 0,33 mmol) in ethanol (8 mL) was added (E)-ethyl 3-(4,4,5,5-tetramethyl-l ;3J2-dioxaborolan-2-yl)acrylate (110 mg, 0.49 mmol), PdCl2(PPh3)2 (20 mg, 0.049 mmol) and KHC03 (170 mg, 0.05 mmol). The reaction was heated to 80 °C for 2 h, cooled to RT, and filtered. The solvent was removed in vacuo. Purification via normal phase silica gel chromatography (CH2Cl2 heptane) provided ((S)-8-(2-amino-6-((R)-l-(4-((E)-3-ethoxy-3-ox^
yl)phenyl)-2,2,2-trifliioiOethoxy)pyrimidin-4-yl)-2-((((2E,4Z)-2-vinylhexa-2,4-dien-l - yl)oxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as a white solid. Step 2: To a solution of ((S)-8-(2-amino-6-((R)-l -(4-((E)-3-ethoxy-3-oxoprop-l -en-l-yl)-2-(3- methyl-lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoiOethoxy)pyrimidin-4-yl)-2-((((2EJ4Z)-2- vinylhexa-2,4-dien-l-yl)oxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (180 mg, 0.15 mmol) in MeOH (5 mL) was hydrogenated in an H-Cube apparatus using a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 mL/min at RT. The resulting eluent was concentrated in vacuo and the product was purified by column chromatography using an Isco Gold reversed phase silica cartridge (100% CH2C12 to 90:9:1 CH2Cl2: eOH:conc. NH4OH) to provide the title compound as a white solid.
1H N R (400 MHz, MeOH-d4): δ ppm 1.14 (t, J=7.15 Hz, 3 H) 1.50 - 1.68 (m, 4 H) 1.94 - 1.99 (m, 2 H) 2.04 (dd, J=13.45, 7.20 Hz, 1 H) 2,30 (dd, J=13.47, 9.27 Hz, 1 H) 2.35 (s, 3 H) 2.66 (t, J=7.54 Hz, 2 H) 2.97 (t, J=7.52 Hz, 2 H) 3.07 - 3.14 (m, 1 H) 3.23 (d, J=l 1.76 Hz, 1 H) 3.39 - 3.72 (m, 4 H) 4.01 - 4.1 1 (m, 3 H) 5.70 (s, 1 H) 6,36 (d, J=2.34 Hz, 1 H) 6.72 (q, J=6.72 Hz, 1 H) 7,27 (d, J=1.61 Hz, 1 H) 7.35 (dd, J=8.15, 1.61 Hz, 1 H) 7.62 (d, J=8.05 Hz, 1 H) 7.83 (d, J=2.34 Hz, 1 H), LCMS (MH+): 632.1
Example lOd: (S)-8-(2-amino-6-((R)-l-(4-chloro-2-(3-mcthyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000126_0001
Step 1: To a solution of (1Κ)-1-[4-ο1ι1οΐΌ-2-(3-Γηε^1ργι* ζο1-1^1)ρ1ΐ6ηγ1]-2}2,2-{ΐ'ίΓΊυοΐΌ- ethanol (40 g, 138 mmol) in dioxane (400 mL) was added 4,6-dichloiOpyrimidin-2-amine (113 g, 690 mmol) and Cs2C03 (132 g, 405 mmol). The mixture was heated for 24 h at 80 °C. The reaction was then cooled to RT and filtered. The solvent was removed in vacuo, then CH2Ch and heptane was added. The solvent volume was reduced until a solid precipitated out. The solid was filtered and the procedure repeated several times to provide 4-chloro-6-[(lR)-l-[4-chforo-2- (3-methylpyrazol-l-yl)phenyl]-2,2;2-trifluoro-ethoxy]pyrimidin-2-amine as a white solid. Step 2: To a solution of 4-chloro-6-[(lR)~l -[4-chloro-2-(3-methylpyrazol-l-yl)phenyl]-2,2,2- trifluoroethoxy]pyrimidin-2-amine (57.3 g, 137 mmol, Step 1 ) in dioxane (500 mL) was added (S)-2-benzyl 3-ethyl 2,8-diazaspii [4,5]decane-253-dicarboxylate (48 g, 124,9 mmol), and NaHCOs (31.5 g, 375 mmol). After 5 h, an additional amount of NaHC03 (31.5 g, 375 mmol) was added and the reaction mixture was heated to 90 °C for 36 h. The reaction was then cooled to RT and filtered. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-benzyI 3-ethyl 8-(2-amino-6-((R)-l-(4-chioro-2-(3-methyl-lH-pyrazol-l -yl)phenyI)-2}2,2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-2,3-dicarboxylate as a white solid.
Step 3: N-CBZ Deprotection was accomplished via method B to provide (S)-ethyl 8-(2-amino-6- ((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2J2-trifiuoroethoxy)pynmidin-4-yl)- 2;8-diazaspiro[4.5]decane-3-carboxylate an off-white solid.
Step 4: Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-l -(4-chloro-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provided the title compound as an off-white solid. Using the generic scheme below, the following examples of Table 3a were prepared as described above for (S)-8-(2-amino-6-((R)-l-(4-chloiO-2-(3-methyl-lH-pyrazol-l-yl)phenyl)- 2,2,2-trifluoroethoxy)pyi'imidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid (Example lOd).
Figure imgf000127_0001
Table 3a,
Figure imgf000127_0002
* Stereochemistry defined in name in table beiow
Figure imgf000127_0003
diazaspiro[4,5]decane-3-carboxylic acid
10b H CI H 8-(2-amino-6-((R)- 1 -(4-chloro-2-(3-meihyl- 1 Pi566 py razol- 1 -yl)phenyl)-2,2,2- lrifluoiOethoxy)pyrimidin-4-yl)-2)8- diazaspiro[4.5]decane-3-caiboxylic acid
10c II CI H (R)-8-(2-amino-6-((R)-l-(4-chloro-2-(3-meihyl-lH- 566 pyrazol- 1 -yl)phenyl)-2,2,2- trifluoi e†hoxy)pyrimidin-4-yl)-2,8- diazaspiio[4,5]decane-3-carboxylic acid
R-Spiro
l Od H CI H (S)-8-(2-amino-6-((R)-l -(4-chloro-2-(3-methyl-l H- 566 pyrazol- l-yl)phenyl)-2,2,2- trifmoroe thoxy)py ri m idin- 4-y 1) -2, 8 - diazaspiro[4.5]decane-3-caiboxylic acid lOe H H H (S)-8-(2-ammo-6-((R)-2,2,2-tnfluoro~ 1 -(2-(3-methyl- 532
1 H-pyrazo 1- 1 -yl)phenyl)et hoxy)pyrimidi n- 4-y 1) -2, 8- diazaspiro [4.5] dec ane -3 -carboxy 1 ic acid
lOf H H CI (S)-8-(2-amino-6-((R)-l-(3-chloro-2-(3-methyl-lH- 566.9 pyrazol- 1 -yI)phenyl)-2,2,2- trifluoroethoxy)pyrimidin- 4-y 1) -2,8- diazaspiro [4.5]decane-3 -carboxylic acid
10g II CF3 H (S)-8-(2-amino-6-((R)-2,2)2-tiifluoiO-l-(2-(3-methyl- 600.6 lH-pyrazol-l-yl)-4-
(tvifluoiOmetliyl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiiO[4.5]decane-3-cai'boxylic acid
lOh H CH3 H (S)-8-(2-amino-6-((R)-252,2-trifluoiO- 1 -(4-methyl-2- 546.6
(3-methyl- lH-pyrazol-1 -yl)phenyl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspii'o[4.5]decane-3-carboxylic acid lOi H F H 8-(2-amino-6-((R)-2}2,2-trifluoiO-l-(4-fiuoi -2-(3- 550.5 methyl- IH-pyrazol- 1 -yl)phenyl)ethoxy)pyrimidin-4- y 1 )-2,8 -diazaspiro [4.5 ]decane-3 - carboxy 1 ic acid
lOj H H 8-(2-amino-6-((R)-2)2)2-trifluoro-l-(4-methoxy-2-(3- 564.6 methyl- IH-pyrazol- 1 -yl)phenyl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.53decane-3-carboxylic acid
10k CI H H 8-(2-amino-6-((R)-l -(5-chloro-2-(3-methyl- 1H- 566.9 py razo 1- 1 -yl)pheny 1) -2,2,2- trifluoroetlioxy)pyrimidin-4-yl)-2,8- diazaspiiO[4.5]decane-3-carboxylic acid
101 H H (S)-8-(2-amino-6-((R)-252,2-trifluoi -l-(4-methoxy- 564.6
2-(3 -methyl- 1 H-pyrazol- 1 - y l)phenyl)ethoxy)py rimidin-4 -y 1 ) -2 , 8 - diazaspiro [4.5] decane- 3 -c arb oxy 1 ic acid 10m H Br H (S)-8-(2-amino-6-((R)-l-(4-bromo-2-(3-methyl-lH- 611 pyrazol - 1 -yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yi)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
10n Br H H (S)-8-(2-amino-6-((R)- 1 -(5-bromo-2-(3-methyl- 1 H- 61 1.5 pyrazol-1 -yI)phenyl)-2,2,2- tiifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiiO[4.5]decane-3-carboxylic acid
Table 3b,
NMR Data for Compounds of Table 3a
Figure imgf000129_0001
10h Ή NMR (400 MHz, MeOH-d4): δ ppm 1 ,58 (t, J=5.25 Hz, 4 H) 2.05 (dd, J=13.45, 7.15 Hz, 1 H) 2.30 (dd, jMl .OO Hz, 1 H) 2.37 (s, 3 H) 2.40 (s, 3 H) 3.05 - 3.17 (m, 1 H) 3.21 - 3.29 (m, 1 H) 3.36 - 3.75 (m, 4 H) 4.09 (dd, J=9.10, 7.25 Hz, 1 H) 5.73 (s, 1 H) 6.37 (d, J=2.25 Hz, 1 H) 6.71 (d, J=6.69 Hz, 1 H) 7.23 (d, J=0.68 Hz, 1 H) 7.31 (d, J=8.10 Hz, 1 H) 7.60 (d, J=8. 05 Hz, 1 H) 7.84 (d, J=2.29 Hz, 1 H)
10Ϊ !H NMR (400 MHz, MeOH-d4): δ pm 1.52 - 1.91 (m, 4 H) 2.05 - 2.16 (m, 1 H) 2.40 (s, 3 H) 2.45 - 2.69 (m, 1 H) 3.52 - 4.13 (m, 4 H) 4.57 (d, J=17.28 Hz, 1 H) 6.43 (d, J=2.25 Hz, 1 H) 6.88 - 7.09 (m, 1 H) 7.23 - 7.51 (m, 2 H) 7.68 - 7.83 (m, 1 H) 7.92 (d, J=2.29 Hz, 1 H)
lOj ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.59 (d, J=4.54 Hz, 4 H) 2.00 - 2.12 (m, 1 H) 2.27 - 2.35 (m, 1 H) 2.38 (s, 3 H) 3.05 - 3.17 (m, 1 H) 3.25 (d, J=l 1.71 Hz, 1 H) 3.48 (dd, J=1.17, 0.20 Hz, 2 H) 3.66 (d, J=5.52 Hz, 2 H) 3.85 (s, 3 H) 4.08 (dd, J=9.08, 7.27 Hz, 1 H) 5.72 (s, 1 H) 6.38 (d, J=2.29 Hz, 1 H) 6.67 (d, J=6.69 Hz, 1 H) 6.94 (d, J=2.64 Hz, 1 H) 7.06 (dd, J=8.83, 2.59 Hz, 1 H) 7.63 (d, J=8.83 Hz, 1 H) 7.87 (d, J=2.29 Hz, 1 H)
10k Ή NMR (400 MHz, CHLOROFORM-d): δ ppm 1.18-1.36 (m, 3 H) 1.43 (t, J=6.74 Hz, 3 H) 1.54-2.29 (m, 6 H) 2.39 (br.s., 3 H) 3.78 (br. s., 4 H) 4.26 (br. s., 2 H) 4.42 (d, J =6.15 Hz, 2 H) 5.53 (br. s., 1 H), 6.36 (s, 1 H) 6.59 (br. s., 1 H) 7.48 (d, J=7.96 Hz,l H), 7.61 (br. s. 1 H) 8, 16 (d, J =8.05 Hz, 1 H) 8.34 (br. s., 1 H)
101 ¾ NMR (400 MHz, DICHLOROMETHANE-d2): δ ppm 1.40 - 1.61 (m, 4 H) 1.95 (dd, J=12.89, 5.86 Hz, 1 H) 2.14 - 2.28 (m, 1 H) 2.36 (s, 3 H) 3.07 (d, J=1.00 Hz, 1 H) 3.16 (d, J=1.00 Hz, 1 H) 3.36 (br. s., 2 H), 3.54 (br. s., 2 H) 3.79 (s, 3 H) 4,08 (t, J=7.71 Hz, 1 H) 4.71 - 5.04 (m, 2 H) 5.47 (s, 1 H) 6.30 (d, J=2.10 Hz, 1 H) 6.65 (q, J=7.i l Hz, 1 H) 6.87 (d, J=2.64 Hz, 1 H) 6.95 (dd, J=8.86, 2,61 Hz, 1 H), 7.61 (d, J=8.74 Hz, 1 H) 7.65 (d, J=2.20 Hz, 1 H)
10m ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.64 (d, J=4.69 Hz, 4 H) 2.03 - 2.15 (m, 1 H) 2.40 (s, 4 H) 3.12 - 3.31 (m, 2 H) 3.43 - 3.63 (m, 2 H) 3.64 - 3.78 (m, 2 H) 4.16 - 4.34 (m, 1 H) 6.43 (d, J=2.34 Hz, , 1 H) 6.76 - 6.91 (m, 1 H) 7.67 (dd, J=5.76, 4.20 Hz, 3 H) 7.94 (d, J=2.15 Hz, 1 H)
10η Ή NMR (400 MHz, DMSO-d6): δ ppm 1 ,47 - 1.71 (m, 4 H) 1.90 (dd, J=13.15, 9.15 Hz, 1 H) 2.24 - 2.39 (m, 4 H) 3.13 (t, J=5.25 Hz, 2 H) 3.66 (br. s., 4 H) 4.39 - 4.51 (m, 2 H) 6.05 (s, 1 H) 6.42 (d, J=2,34 Hz, 1 H) 7.25 (d, J=5.27 Hz, 1 H) 7.51 (d, J=8.59 Hz, 1 H) 7.78 (s, 1 H) 7.85 (dd, J=8.54, 2.29 Hz, 1 H) 8.11 (d, J=2.34 Hz, 1 H) 8.95 (d, J=6.69 Hz, 1 H) 10.20 (br. s., 1 H)
Example 10ο: (S)-8-(2-amino-6-((R)-l-(4-bromo-2-(3-methyl-lH-pyrazol-l-yI)phenyl)-2,2,2- trifluorocthoxy)pyrimidiu- -yl)-2,8-diazaspiro[4.5Jdecane-3-carboxyIic acid
Figure imgf000130_0001
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-l -(4-chloro-2-(3- methyl-lH-pyiazol-l-yl)phenyl)-2>2,2-trifluotOethoxy)pyrimidin-4-yl)-2J8- diazaspiro[4.5]decane-3-carboxylic acid (Example lOd) starting with (R)-l-(5-bromo-[l,r- biphenyl]-2-yl)-2,2,2-trifluoroethanol (Intermediate 38). H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 7.7 Hz, 2H), 1.61 (q, J = 6.5, 5.3 Hz, 4H), 2.06 (dd} J = 13.5, 7.4 Hz, 1H), 2.36 (dd, J = 13.5, 9.1 Hz, 1H), 3.15 (d, J = Π .9 Hz, 1H), 3.26 (d, J = 1 1.7 Hz, 1H), 3.47 (ddt, J - 21.7, 13.4, 5.8 Hz, 2H), 3.63 (m, 2H), 4.18 (t, J = 8.2 Hz, 1H), 6.63 (q, J = 6.8 Hz, 1H), 7.50 (m, 7H). LCMS (MH+): 607.
Example lOp: (S)-8-(2-amino-6-((R)-l-(4-chloro-2-(3-(trifluoiOmethyl)-lH-pyrazoi-l- yl)phenyl)-2,2,2-trifluoiOCthoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000131_0001
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-l -(4-chloro-2-(3- methyl-lH-pyrazol-l -yl)phenyl)-2,2,2-triiluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5] decane-3-carboxylic acid (Example lOd) starting with (R)-l-(4-chIoro-2-(3-(trifluoromethyi)- 1 H-pyrazol- 1 -yl)phenyl)-2,2,2-trifiuoiOethanol (Intermediate 39). l NMR (400 MHz, MeOH-d4): δ ppm 1.53 (d, J=5.08 Hz, 4 H) 1.77 - 1.87 (m, 1 H) 2,03 - 2.20 (m, 1 H) 2.75 (s, 1 H) 2.99 (s, 1 II) 3.37 -3.53 (m, 2 H) 3.54 - 3.66 (m, 2 H) 3.66 - 3.77 (m, 1 H) 5,56 (s, 1 H) 6.53 - 6.70 (m, 1 H) 6.96 (d, J=2.34 Hz, 1 H) 7.62 (dd, J=4.30, 2.34 Hz, 2 H), 7.76 (s, 1 H) 8.25 (d, J=1.37 Hz, 1 H). LCMS (MH+): 620. Example lOpa: (S)-8-(2-amino-6-((R)-l-(2-(3-(tert~bufyl)-lH-pyrazoI-l-yl)-4-chlorop enyl)- 2,2,2-trifluoroethoxy)pyrimidin-4- l)-2,8-diazaspiro[4.5]tlecane-3-carboxylic acid
Figure imgf000132_0001
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-l-(4-chloro-2-(3- methyl- 1 H-pyrazol-1 -yl)phenyl)-2,2,2-trifluoiOethoxy)pyrimidin-4-yI)-2J8-diazaspiiO[4.5] decane-3-carboxylic acid (Example lOd) starting with (R)-l-(2-(3-(tert-butyl)~lH-pyrazol-l-yl)- 4-chlorophenyl)-2,2,2- fluoroethanol (Intermediate 40).
Ή NMR (400 MHz, MeOH-d4): δ ppm 1.40 (s, 9 H) 1.51 - 1.68 (m, 4 H) 1.99 - 2.12 (m, 1 H) 2.25 - 2.41 (m, 1 H) 3.05 - 3.16 (ra, 1 H) 3.20 -3.28 (m, 1 H) 3.38 - 3.55 (m, 2 H) 3.56 - 3.73 (m, 2 H) 4.00 - 4.16 (m, 1 H) 5.57 (s, 1 H) 6.52 (d, J=2.34 Hz, 1 H) 7.15 - 7.28 (m, 1 H) 7.44 - 7.53 (m, 1 H) 7.56 (d, J=1.95 Hz, 1 H) 7.68 - 7.79 (m, 1 H) 7.95 (d, J=2.34 Hz, 1 H). LCMS (MH+): 609. Example lOq: (S)-8-(2-amino-6-((R)-l-(4-chloro-2-(3-isopropyl-lH-pyrazol-l-yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidiii-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000132_0002
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-l-(4-chloro-2-(3- methyl-lH-pyrazol-l-yl)phenyl)-2,2J2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5] decane-3-carboxylic acid (Example lOd) starting with (R)-l-(4-chloiO-2-(3-isopropyl-lH- pyrazol- 1 -yl)phenyl)~2,2,2-trifluoiOethanol (Intermediate 41). lB NMR (400 MHz, MeOH-d4): δ ppm 1.36 (dd, J=6.93, 1.07 Hz, 6 H) 1.57 (br. s.} 4 H) 1.86 - 2.03 (m, 1 H) 2.15 - 2.30 (m, 1 H) 2.86 - 3.00 (m, 1 H) 3.02 - 3.19 (m, 2 H) 3.39 - 3.55 (m, 2 H) 3.57 - 3.73 (m, 2 H) 3.82 - 3.98 (m, 1 H) 5.63 (s, 1 H) 6.40 - 6.56 (m, 1 H) 6.93 - 7.10 (m, 1 H) 7.54 (s, 2 H) 7.67 - 7.78 (m, 1 H) 7.91 - 8.02 (m, 1 H). LCMS (MH+): 595.
Example lOr: (S)-8-(2-amino-6-((R)-l-(4-chloro-2-(3-cyclopropyl-lH-pyrazol-l-yl)phenyl)- 2,2,2-trifluorocthoxy)pynmidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carbox lic acid
Figure imgf000133_0001
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-l-(4-chloro-2-(3- methyl- 1 H-pyrazol- 1 -yl)phenyl)-2,2,2-trifluoi'oethoxy)pynmidin-4-yi)-2,8-diazaspii [4.5] decane-3-carboxylic acid (Example lOd) starting with (R)-l-(4-chloro-2-(3-cyclopropyl-lH- pyrazol- 1 -yl)phenyl)-2,2,2-trifluoroethanol (Intermediate 42). H NMR (400 MHz, MeOH-d4): δ ppm 0.77 - 0.90 (m, 2 H) 0.95 - 1.08 (m, 2 H) 1.49 - 1.65 (m, 4 H) 1.80 - 1.95 (m, 1 H) 1.99 - 2,10 (m, 1 H) 2.10 - 2.24 (m, 1 H) 2.74 - 2.85 (m, 1 H) 3.00 - 3.1 1 (m, 1 H) 3.38 - 3.69 (m, 4 H) 3.72 - 3.84 (m, 1 H) 5.56 - 5.70 (m, 1 H) 6.29 - 6.38 (m, 1 H) 6.89 - 7.05 (m, 1 H) 7.52 (s, 2 H) 7.67 - 7.77 (m, 1 H) 7.86 - 7.98 (m, 1 H), LCMS (MH+): 593.
Example 11: (S)-8-(2-amino-6-((R)-2)2,2-trifluoro-l-(6-methyl-2-(3-inethyl-lH-pyrazol-l- yl)pyridin-3-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000134_0001
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-l -(4-chloro-2-(3- met yl- 1 H-py razol - 1 -yl)pheny 1) -2,2 ,2-trifluoroethoxy)pyr i midin-4-y l)-2 , 8 - diazaspiro[4.5]decane-3-carboxylic acid (Example lOd) starting with (S)-2,2,2-trifluoro-l-(6~ methyl-2-(3-methyl-lH-pyrazol-l -yl)pyridin-3-yl)ethanol (Intermediate 20)
Example 12a: (S)-8-(2-amino-6-((R)-l-(4-ethyl-2-(3-methyl-lH-pyrazoI-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000134_0002
Step J : To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l-(4-bi mo-2-(3-methyl-lH- pyi zol-l-yl)phenyl)-2,2,2 rifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3- dicarboxylate (300 mg, 0,388 mmol, see Example lu) in EtOH:H20 (15 mL) was added 4,4,5,5- tetramethyl-2- vinyl- 1 ,3,2-dioxaborolane (90 mg, 0.58 mmol), KHC03 (389 mg, 3.88 mmol), and PdCl2(PPh3)2 (41 mg, 0.058 mmol), The reaction mixture was heated to 80 °C for 1 h, then cooled to RT, The reaction was diluted with water, extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. Purification with a 40 g Isco RediSep silica cartridge (EtOAc:heptane) provided (S)-2-benzyl 3- ethyl 8-(2-amino-6-((R)"2,2,2-trifluoro-l -(2-(3-methyl-lH-pyrazol- l-yl)-4- vinylphenyi)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid. Step 2: N-CBZ Deprotection was accomplished via method A, which also reduced the olefin, to provide (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l-(4-ethy)-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyriniidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Step 3: Hydrolysis of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l-(4-ethyl-2-(3-methyl-lH- pyrazol-l-yl)phenyl)-2J2)2-trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4,5]decane-2,3- dicarboxylate using the LiOH general method provided the title compound as a white solid,
Using the same scheme below, the following examples of Table 4a were prepared as described above for (S)-8-(2-amino-6-((R)-l -(4-ethyl-2-(3-methyl-lH-pyrazol-l-yl)phenyl)- 2,2}2-trifIuoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid (Example 1
Figure imgf000135_0001
Table 4a.
Figure imgf000136_0001
Figure imgf000136_0002
Example 13: (3S)-8-(2-amino-6-((lR)-l-(4-(l,2-dihydroxyethyl)-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-tnf!uoroethoxy)pyriinidin-4-yl)-2,8-diazaspiro[4.5]decanc-3-carboxylic acid
Figure imgf000137_0001
Step 1 : To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2;2,2-trifluora- 1 -(2-(3-methyl- lH-pyrazol-l-yl)-4-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3- dicarboxylate (product of Step 1, Example 12b)(373 mg, 0.518 mmol) in 4: 1 acetone:H20 (20 mL) was added Os04 (313 vL of a 4% (w/w) aqueous solution, 325 mg, 0.0518 mmol) and N- methylmorpholine-N-oxide (214 of a 50% (w/w) aqueous solution, 242 mg, 1.04 mmol). The reaction was stirred at RT for 24 h, concentrated in vacuo, and the residue was purified by chromatography on a 50 g Isco Gold RediSep reversed phase silica cartridge (H20:HOAc : 99:1 to EtOH:HOAc 99:1). A second purification on a 40 g Isco RediSep silica cartridge eluting (CH2CI2 100% to 90:9:1 CH2Cl2:EtOH:NH4OH) provided (3S)-2-benzyi 3-ethyl 8-(2-amino-6- ((lR)-l -(4-(l)2-dihydroxyethyl)-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-2,3-dicaiboxylate as a white solid.
Step 2: N-CBZ deprotection was accomplished via method A to provide (3S)-ethyl 8-(2-amino- 6-((l R)-l-(4-(l,2-dihydroxyethyl)-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2}2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a white solid,
Step 3 Hydrolysis of (3S)-ethyl 8-(2-amino-6-((lR)-l-(4-(l,2-dihydroxyethyl)-2-(3-methyl-lH- pyrazol-l-yl)phenyl)-2,2}2-trifluoiOethoxy)pyrimidin-4-yl)-2}8-diazaspiro[4.5]decane-3- carboxylate using the LiOH general method provides the title compound as a white solid. Ή NMR (400 MHz, MeOH-d4): δ ppm 1.49 - 1.66 (m, 4 H) 2.05 (dd, J=13.50, 7.20 Hz, 1 H) 2.31 (dd, J=13.45, 9.20 Hz, 1 H) 2.38 (s, 3 H) 3,04 - 3.28 (m, 2 H) 3.38 - 3.76 (m, 6 H) 4.08 (dd, J-8.98, 7.27 Hz, 1 H) 4.67 - 4.79 (m, 1 H) 5.72 (d, J=2.15 Hz, 1 H) 6.39 (d, J=2.29 Hz, 1 H) 6.77 (q, J=6.65 Hz, 1 H) 7.45 (s, 1 H) 7.52 (d, J=8.20 Hz, 1 H) 7.71 (d, J=8.15 Hz, 1 H) 7.88 (dd, J=4.20, 2.34 Hz, 1 H). LCMS (MH+): 592. Example 14: (S)-8-(2-amino-6-((R)-l-(4-cyano-2-(3-methyl-lH-pyrazoI-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5Jdecane-3-carboxylic acid
Figure imgf000138_0001
Step 1 : To a solution of (3S)-2-benzyl 3-ethyl 8-(2-amino-6-(l-(4-chloi -2-(3-methyl-lH- pyrazol-l-yl)phenyl)-2,2,2-tnfluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-2,3- dicarboxylate (730 mg, 1.0 mmol), was added ZnCN2 (280 mg, 2.4 mmol), Zn (64 mg, 1.0 mmol), DMA (10 mL), and Pd(P-t-Bu3)2 (78 mg, 0.15 mmol). The reaction mixture was heated in a sealed vial at 1 15 °C for 2 h, then cooled to RT, filtered, and concentrated in vacuo.
Purification by normal phase silica gel column (EtOAc/hepate) provided (3S)-2-benzyl 3-ethyl 8-(2-amino-6-(l ~(4-cyano-2-(3-methyl- IH-pyrazol- 1 -yl)phenyl)-2,2,2-trifluoroetlioxy) pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a viscous oil.
Step 2: N-CBZ Deprotection was accomplished via Method A to provide (3S)-ethyl 8-(2-amino- 6-( 1 -(4-cyano-2-(3-methyl- IH-pyrazol- 1 -yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2J8- diazaspiro[4.5]decane-3-carboxylate as an off-white solid.
Step 3: Hydrolysis of (3S)-ethyl 8-(2-amino-6-(l -(4-cyano-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2J8-diazaspiro[4,5]decane-3-carboxylate using the LiOH general method provides the title compound as an off-white solid. 'H NMR (400 MHz, MeOH-d-t): δ ppm 1.47 - 1.71 (m, 4 H) 1.95 - 2.10 (m, 1 H) 2.20 - 2.33 (m, 1 H) 2.36 (s, 3 H) 2.96 - 3.24 (m, 2 H) 3.35 - 3.54 (m, 2 H) 3.55 - 3.79 (m, 2 H) 3.92 - 4.13 (m, 1 H) 5.65 (s, 1 H) 6.42 (d, J=2.15 Hz, 1 H) 6.95 (q, J=6.72 Hz, 1 H) 7.70 - 7.91 (m, 3 H) 7.97 (d, J=2,25 Hz, 1 H). LCMS (MH+): 556.
Example 15: (S)-8-(2-amino-6-(( )-l-(4-carbamoyI-2-(3-inethyI-lH-pyrazol-l-yl)phenyI)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000139_0001
Step 1 : To a solution of (3S)-2-benzyl 3-ethyl 8-(2-amino-6-(l-(4-cyano-2-(3-methyl-lH- pyrazol- 1 -yl)phenyl)-2,2,2-trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-2,3- dicarboxylate (150 mg, 0.2 mmol, see Ex. 14) in toluene (10 mL) was added acetaldehyde oxime (240 mg, 4 mmol) and InCb (44 mg, 0.2 mmol). The reaction was heated to 110 °C for 3 h, then cooled to RT, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/hepate) provided (3S)-2-benzyl 3-ethyl 8-(2-amino-6-(l -(4-carbamoyl-2-(3-methyl-lH- pyrazol-l-yl)phenyl)-2,2,2-tnfiuoi ethoxy)pyrimidin-4-yl)-2)8-diazaspiiO[4.5]decane-2,3- dicarboxylate as a white solid,
Step 2: N-CBZ Depiotection was accomplished via Method A to provide (3S)-ethyl 8-(2-amino- 6-(l-(4-carbamoyl-2-(3-methyi-lH-pyrazol-l-yl)phenyl)-2,2}2-trifluoiOethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate as a white solid.
Step 3: Hydrolysis of (3S)-ethyl 8-(2-amino-6-(l-(4-carbamoyl-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2)2-trifluoiOethoxy)pyrimidin-4-yl)~2,8-diazaspiiO[4.5]decane-3-carboxylate using the LiOH general method provides the title compound as a white solid. Ή NMR (400 MHz, MeOH-dt): 6 ppm 1.56 (t, J=4.98 Hz, 5 H) 2.03 (dd, J=13.47, 7.03 Hz, 1 H) 2.23 - 2.33 (m, 2 H) 2.35 - 2.39 (m, 3 H) 3.04 - 3.12 (m, 1 H) 3.22 (d, J=l 1.71 Hz, 1 H) 3.37 - 3.72 (m, 5 H) 4.05 (dd, J=9.20, 7.05 Hz, 1 H) 5.70 (s, 1 H) 6.40 (d, J=2.39 Hz, 1 H) 6.82 - 6.92 (m, 1 H) 7.80 (d, J=8.10 Hz, 1 H) 7.87 - 7.97 (m, 4 H). LCMS (MH+): 575.
Example 16: (S)-8-(2-amino-6-((R)-l-(4-carboxy-2-(3-methyl-lH-pyrazoI-l-yl)phenyl)- 2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxyIic acid
Figure imgf000140_0001
Step 1: To a solution of (3S)-2-benzyl 3-ethyl 8-(2-amino-6-(l-(4-cyano-2-(3-methyl-lH- pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-2,3- dicarboxylate (0.35 g , 0.50 mmol, see Ex. 14) in MeOH (5 mL) and water (1 mL) was added LiOH-H20 (0.20 g, 5 mmol). The mixture was heated to 50 °C overnight. The reaction was then cooled to RT, and the reaction was acidified with 6N HC! to pH=l , Concentration in vacuo followed by reverse phase HPLC purification (MeOH/water/HOAc) provided (3S)-8-(2-amino- 6-(l -(4-carboxy-2-(3-methyl- 1 H-pyrazol- 1 -yl)phenyl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2- ((benzyloxy)carbonyl)-2,8-diazaspiro[4,5]decane-3-carboxylic acid as a white solid.
Step 2: N-CBZ Deprotection was accomplished via Method A to provide the title compound as a white solid.
Ή NMR (400 MHz, MeOH-d4): δ ppm 1.57 (t, J=5.42 Hz, 4 H) 2.03 (dd, J=l 3.42, 7.42 Hz, 1 H) 2.25 - 2.35 (m, 2 H) 2.37 (s, 2 H) 3.04 -3.13 (m, 1 H) 3.16 - 3.25 (m, 1 H) 3.38 - 3.75 (m, 5 H) 4.06 (dd, 1=9.03, 7.32 Hz, 1 H) 5.72 (s, 1 H) 6.39 (d, J=2.29 Hz, 1 H) 6.78 - 6.89 (m, 1 H) 7.76 (d, J=8.15 Hz, 1 H) 7.90 (d, J=2.34 Hz, 1 H) 7.95 (d, J=1.42 Hz, 1 H) 8.04 (dd, J=8.13, 1.59 Hz, 1 H). LCMS (MH+): 576. Example 17: (S)-8-(2-amino-6-((R)-l-(4-(ethoxycarbonyl)-2-(3-methyl-lH-pyrazoI-l- yl)phenyI)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5](lecane-3-carboxyIic acid
Figure imgf000141_0001
Step 1 : To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l-(4-bromo-2-(3-methyl-lH- pyrazol-l-yl)phenyl)-2,2,2-tnfluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-2,3-- dicarboxylate (1.50 g, 1.94 mmol, See Ex. hi) in THF (20 niL), MeOH (10 niL) and water (10 niL) was added LiOH-H20 (0.80 g, 19.4 mniol), and the reaction was stirred at RT for 4 h. The pH of the reaction mixture was adjusted to 6.5 with 6 N HC1, and the organic solvents were removed in vacuo to provide a white solid that is filtered away. The reaction mixture was then partitioned between water and EtOAc, and extracted. The combined organic layers were washed with brine, dried over Na2S04} filtered, then concentrated in vacuo to provide (2S)-8-[2-amino-6- [(lR)-l-[4-bromo-2-(3-methylpyrazol-l-yl)phenyl]-2,2;2-trifluoiO-ethoxy]pyrimidin-4-yl]-3- benzyloxycarbonyl-3,8-diazaspiro[4.5]decane-2-carboxylic acid as a white solid that is used directly without further purification.
Step 2: To a solution of (2S)-8-[2-amino-6-[(l R)-l-[4-biOmo-2-(3-methylpyrazol-l-yl)phenyl]- 2,2,2-trifluoro-ethoxy]pyrimidin-4-yl]-3-benzyloxycarbonyl-3J8-diazaspiiO[4.5]decane-2- carboxylic acid (74 mg, 0.10 mmol, Step 2) in EtOH (4 mL) was added KHCO3 (84 mg, 1.0 mmol). The reaction mixture was degassed, fitted with a 1 atm CO balloon, then treated with PdCl2(PPh3)2 (1 mg, 0,02 mmol). The reaction was degassed once more with 1 atm CO and then heated to 80 °C for 12 h, The reaction was cooled to RT, concentrated in vacuo and the residue was partitioned between water and EtOAc, and extracted. The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (CH2Cl2/AcOH/EtOH) provided (2S)-8-[2-amino-6-[(lR)-l-[4- ethoxycai*bonyl-2-(3-methy]pyrazoi-l -yl)phenyl]-2,2,2-trifliioro-ethoxy] pyrimidin-4-yl]-3- benzyloxycarbonyl-3,8-diazaspiro[4.5]decane-2-carboxyiic acid as a white solid.
Step 3: N-CBZ Deprotection was accomplished via Method A to provide the title compound as a white solid.
'H NMR (400 MHz, MeOH-d4): δ ppm 1.37 (t, J=7.13 Hz, 3 H) 1.58 (d, 1=4.30 Hz, 4 H) 1.97 (s, 2 H) 2.04 (dd, J=13.47, 7.27 Hz, 1 H) 2.30 (dd, J=13.59, 9.25 Hz, 1 H) 2.38 (s, 3 H) 3.05 - 3.27 (m, 2 H) 3.39 - 3.76 (m, 4 H) 3.99 - 4.10 (m, 1 H) 4.37 (q, J=7.13 Hz, 2 H) 5.68 (s} 1 H) 6.41 (d, J=2.34 Hz, 1 H) 6.84 (q, J=6.67 Hz, 1 H) 7.83 (d, J=8.10 Hz, 1 H) 7.94 (d, J=2.34 Hz, 1 H) 7.99 (d, J=1.61 Hz, 1 H) 8.09 (dd, J=8.27, 1.68 Hz,l H). LCMS (MH+): 604.
Example 18a: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4-(((l,l,l,3,3,3-hexafluoro-2- methyIpropan-2-yI)oxy)carbonyI)-2-(3-methyI-lH-pyrazoI-l-yI)phenyl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxyIic acid
Figure imgf000142_0001
Step 1: To a solution of (S)-8-(2-amino-6-((R)-l-(4-bromo-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,252-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid (product of Step 3, Example 10m) (1.2 g, 1.6 mmol) in DMF ( 16 mL) was added benzyl bromide (0.27 g, 1.6 mmol) and NaHC03 (0,67 g, 8.0 mmol). The reaction was then heated to 60 °C for 2 h, cooled to RT, and stirred for 12 h. The precipitate was filtered, washed with EtOAc and the filtrate concentrated in vacuo. The residue was partitioned between water and EtOAc, and extracted. The combined organic layers were washed with brine, dried over Na2S0 , filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc /heptane) provided (S)-dibenzyl 8-(2-amino-6-((R)-l-(4-bromo-2-(3- methyl- 1 H-pyrazol-1 -yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-2,3-dicarboxylate as the white solid.
Step 2 To a solution of (S)-dibenzyl 8-(2-amino-6-((R)-l-(4-bromo-2-(3-methyl-lH-pyrazol-l - yl)phenyl)-2}2,2-tnfluoiOethoxy)pyi'imidin-4-yi)-2,8-diazaspiiO[4.5]decane-2}3-dicai'boxylate from Step 1 (415 mg, 0,50 mmol) in 1,4-dioxane (8 mL) and water (4 mL) was added KHCO3 (420 mg, 5.0 mmol), and the reaction was degassed with 1 atm CO. Then PdCl2(PPli3)2 ( 140 mg, 0.10 mmol) was added and the reaction mixture was treated with 1 atm CO (balloon). The reaction mixture was heated to 80 °C for 12 h, then cooled to RT, and concentrated in vacuo. The residue was partitioned between water and EtOAc, and extracted. The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo.
Purification by normal phase silica gel column (CH2Cl2/MeOH/NH OH) provided
4-[(lR)-l-[2-amino-6-[(2S)-2,3-bis(benzyloxycarbonyl)-3;8-diazaspiro[4.5]decan-8- yl]pyrimidin-4-yl]oxy-2i2,2-trifluoi -ethyl]-3-(3-met iylpyrazol-l-yl)benzoic acid as a white solid.
Step 3: To a solution of 4-[(lR)-l -[2-amino-6-[(2S)-2,3-bis(benzyloxycarbonyl)-3,8- diazaspii [4.5]decan-8-yl]pyrimidin-4-yl]oxy-2,2;2-trifluoro-ethyl]-3-(3-methylpyrazol-l- yl)benzoic acid (80 mg, 0.1 mmol) in CH2C12 (4 mL) was added DMAP (73 mg, 0.6 mmol), (CF3)2MeCOH (t 08 mg, 0.6 mmol), followed by EDCI (1 14 mg, 0.6 mmol). The reaction mixture was stirred at RT for 12 h, diluted with CH2C12 and washed with water, The aqueous solution was extracted with CH2CI2. The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc / heptane) provided dibenzyl (2S)-8-[2-amino-6-[(lR)-2,2;2-trifiuoro-l-[2-(3- methylpyrazol- 1 -yl)-4-[2,2,2-trifluoro-l -methyl- l-(trifiuoromethyl)ethoxy]carbonyl-phenyl] ethoxy]pyrimidin-4-yl]-3,8"diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Step 4: N-CBZ Deprotection was accomplished via Method A to provide the title compound as a white solid. Using the generic scheme below, the following examples of Table 5a were prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4-(((l,l;l,3,3,3-hexafluoiO~2- methylpi'opan-2-yl)oxy)carbonyl)-2-(3-methyl-lH-pyrazol-l-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2) -diazaspiro[4.5]decane-3-carboxylic acid (Example 18a),
Figure imgf000144_0001
Figure imgf000145_0001
Table 5b.
NMR Data for Compounds of Table 5a
Figure imgf000145_0002
Hz, 2 H) 1.58 (d, J=4.83 Hz, 4 H) 1.68 - 1.82 (m, 2 H) 1.97 (s, 1 H) 2.04 (dd, J=13.52, 7.03 Hz, 1 H) 2.30 (dd, 1=13.42, 9.18 Hz, 1 H) 2.38 (s, 3 H) 3.07 - 3.25 (m, 2 H) 3.38 - 3.71 (m, 4 H) 4.06 (dd, JM9.15, 7.00 Hz, 1 H) 4.33 (t, J=6.61 Hz, 2 H) 5.68 (s, 1 H) 6.42 (d, J=2.39 Hz, 1 H) 6.84 (q, J=6.44 Hz, 1 H) 7.84 (d, J=8.30 Hz, 1 H) 7.95 (d, J=2.29 Hz, 1 H) 7.98 (d, J=1.61 Hz, 1 H) 8.08 (dd, J=8.25, 1.71 Hz, 1 H)
18d !H NMR (400 MHz, MeOH-d4): δ ppm 1.57 (s, 13 H) 1.97 (s, 2 H) 2.04 (dd, J=13.50, 7.15 Hz, 1 H) 2.30 (dd, J=14.06, 9.96 Hz, 1 H) 2.38 (s, 3 H) 3.08 - 3.26 (m, 2 H) 3.38 - 3.74 (m, 4 H) 4.01 - 4.14 (m, 1 H) 5.68 (s, 1 H) 6.41 (d, J=2.34 Hz, 1 H) 6.80 (q, J=6.64 Hz, 1 H) 7.80 (d, J=8.15 Hz, 1 H) 7.92 (dd, J=7.88, 1.93 Hz, 2 H) 8.02 (dd, J=8.27, 1.59 Hz, 1 H)
18e Ή NMR (400 MHz, MeOH-d4): δ ppm 1.00 (d, J=6.74 Hz, 6 H) 1.52 - 1.64 (m, 4 H) 1.97 (s, 2 H) 2.00 - 2.12 (m, 2 H) 2.30 (dd, J=13.45, 9.35 Hz, 1 H) 2.38 (s, 3 H) 3.07 - 3.26 (m, 2 H) 3.37 - 3.55 (m, 2 H) 3.58 - 3.70 (m, 2 H) 4.06 (dd, J=9.03, 7.17 Hz, 1 H) 4.12 (d, J=6.59 Hz, 2 H) 5.68 (s, 1 H) 6.42 (d, J=2.39 Hz, 1 H) 6.84 (q, J=6.51 Hz, 1 H) 7.84 (d, J=8.35 Hz, 1 H) 7.95 (d, J=2.34 Hz, 1 H) 7.98 (d, J=1.61 Hz, 1 H) 8.09 (dd, J=8.27, 1.68 Hz, 1 H)
18f lU NMR (400 MHz, MeOH-d4): δ ppm 1.54 - 1.94 (m, 1 1 H) 1.97 (s, 3 H) 2.04 (dd, J-13.35, 7.15 Hz, 1 H) 2.24 - 2.35 (m, 1 H) 2.38 (s, 3 H) 3.02 - 3.27 (m, 2 H) 3.37 - 3.81 (m, 4 H) 3.95 - 4.22 (m, 1H) 5.32 - 5.44 (m, 1 H) 5.67 (s, 1 H) 6.41 (d, J=2.39 Hz, 1 H) 6.82 (d, J=6.39 Hz, 1 H) 7.82 (d, J=8.30 Hz, 1 H) 7.94 (d, J=1.85 Hz, 2 H) 8.06 (dd, J=8.15, 1.71 Hz, 1 H)
Example 19a: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(2-(3-methyl-lH-pyrazoI-l-yl)-5- viiiylphenyl)cihoxy)pyrimidin-4- -2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000146_0001
Step l To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l-(5-bromo-2-(3-methyl-lH- pyrazol-l-yl)phenyl)-2,2J2-ti'ifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-2)3- dicarboxylate (500 mg, 0.65 mmol) in 4:1 EtOH:H20 (25 mL) was added 4,4,5,5-tetramethyl-2- vinyl-l ,3,2-dioxaboiOlane (150 mg, 0.971 mmol), KHCO3 (648 mg, 6.47 mmol), and
PdCl2(PPh3)2 (68 mg, 0.097 mmol). The reaction mixture was heated to 80 °C for 1.75 h, then cooled to RT, and extracted with EtOAc. The combined organic layers were washed with brine, dried ove Na S0 , filtered, and concentrated in vacuo. Purification via a 40 g Isco RediSep silica cartridge eluting (EtOAc/hepate) provides (S)-2-benzyl 3-ethyl 8~(2-amino-6~((R)-2,2s2- trifluoro-l-(2-(3-methyl-lH-pyrazol-l-yl)-5-vinyIphenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid. Step 2: N-CBZ Deprotection was accomplished via Method B to provide (S)-ethyl 8-(2-amino-6- ((R)-2,2,2-trifluoi - 1 -(2-(3-methyl- IH-pyrazol- 1 -yl)-5-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate as an off-white solid.
Step 3: Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoiO-l-(2-(3-methyl- l H-pyrazol-l- yl)-5-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decaiie-3-carboxylate using the LiOH general method provided the title compound as a white solid.
Using the generic scheme below, the following examples of Table 6a were prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifiuoiO- 1 -(2-(3-methyl- IH-pyrazol- 1 -yl)-5- v d (Example 19a).
Figure imgf000147_0001
Table 6a.
Figure imgf000148_0001
Figure imgf000148_0002
Table 6b.
NMR Data for Compounds of Table 6a
Figure imgf000148_0003
4.07 (dd, J=9.10, 7.20 Hz, 1 Η) 5.76 (s, 1 Η) 6.40 (m, 3 H) 6.76 (m, 1 H) 7.33 (d, J=8.25 Hz, 1 H) 7.54 (dd, J=8.30, 2.05 Hz, 1 H) 7.66 (s, 1 H) 7.84 (d, J=2.29 Hz, 1 H)
19d lH NMR (400 MHz, MeOH-d4): δ ppm 1.57 (t, J=5.44 Hz, 4 H) 1.97 (s, 3 H) 2.04 (dd, J=13.72, 7.27 Hz, 1 H) 2.30 (dd, J=13.32, 9.18 Hz, 1H) 2.37 (s, 3 H) 3.07 - 3.25 (m, 2 H) 3.40 - 3.55 (m, 2 H) 3.65 (dd, J=9.27; 4.73 Hz, 2 H) 4.07 (t, J=7.98 Hz, 1 H) 5.75 (s, 1 H) 6.40 (d, J=2.34 Hz,l H) 6.51 (d, J=16.20 Hz, 1 H) 6.94 (q, J=6.52 Hz, 1 H) 7.46 (d, J=8.30 Hz, 1 H) 7.66 (d, J=15.86 Hz, 1 H) 7.78 (dd, J=8.32, 1.88 Hz, 1 H) 7.87 (s, 1 H) 7.92 (d, J=2.34 Hz, 1 H)
Using the generic scheme beiow, the following examples of Table 7a can be prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifiuoiO-l-(2-(3-methyl-lH--pyrazol-l-yl)-5- vinylphenyl)ethoxy)pyrimidin-4-yI)-2,8-diazaspiro[4.5]decane-3-caiboxylic acid (Example 19a), by substituting the alkylidene borolane with a boronic acid or ester.
Figure imgf000149_0001
Figure imgf000149_0002
Figure imgf000150_0001
Figure imgf000151_0001
Table 7b.
NMR Data for Compounds of Table 7a
Figure imgf000151_0002
4,08 (dd, J=9.08, 7.27 Hz, 1 H) 5.79 (s, 1 H) 6.42 (d, J=2.29 Hz, 1 H) 6.86 - 7.01 (m, 1 Η) 7.53 (d, J=8,30 Hz, 1 H) 7.64 - 7,77 (m, 2 H) 7.85 (dd, J=8.30, 2.15 Hz, 1 H) 7,94 (d, J=2.34 Hz, 1 H) 7.99 (d, J=1.32 Hz, 1 H) 8.08 - 8.18 (m, 2 H)
h *H NMR (400 MHz, MeOH-d4): δ ppm 1.59 (t, J=5.54 Hz, 4 H) 2.04 (dd, J=13.45, 7.39 Hz, 1 H) 2.32 (dd, J=13.50, 9.25 Hz, 1 H) 2.41 (s, 3 H) 3.07 - 3.26 (ra, 2 H) 3.41 - 3.76 (m, 4 H) 4.08 (dd, J=9.01, 7.30 Hz, 1 H) 5.81 (s, 1 H) 6.42 (d, J=2.29 Hz, 1 H) 6.57 (d, J=16.01 Hz, 1 H) 6.86 - 6.97 (m, 1 H) 7.48 - 7.57 (m, 2 H) 7.60 - 7,68 (m, 2 H) 7.73 (d, J=16.01 Hz, 1 H) 7.77 (bs, 1 H) 7.83 (dd, J=8.25, 2.10 Hz, 1 H) 7.93 - 7.96 (m, 2 H)Ϊ ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.50 - 1.65 (m, 4 H) 2.05 (dd, J=13.45, 7.20 Hz, 1 H) 2.31 (dd, J=13.40, 9.30 Hz, 1 H) 2.40 (s, 3 H) 3.05 - 3.28 (m, 2 H) 3.40 - 3,74 (m, 4 H) 4.07 (dd, J=9.10, 7.25 Hz, 1 H) 5.79 (s, 1 H) 6.42 (d, J=2.29 Hz, 1 H) 6.54 (d, J=16.01 Hz, 1 H) 6.91 (q, J=6.72 Hz, 1 H) 7.51 (d, J=8.25 Hz, i H) 7.61 - 7,75 (m, 5 H) 7.82 (dd, J=8.30, 2.15 Hz, 1 H) 7.93 (d, J=2.34 Hz, 1 H) 7.97 (s, 1 H)
j ¾ NMR (400 MHz, MeOH~d4): δ ppm 1.51 - 1.66 (m, 4 H) 2.04 (dd, J=13.50, 7.15 Hz, 1 H) 2.31 (dd, J=13.37, 9.18 Hz, 1 H) 2.40 (s, 3 H) 2.65 (t, J=7.61 Hz, 2 H) 2.99 (t, J=7.59 Hz, 2 H) 3,06 - 3.27 (m, 2 H) 3.40 - 3.78 (m, 4 H) 4,08 (dd, J=8.98, 7.42 Hz, 1 H) 5,80 (s, 1 H) 6.41 (d, J=2.34 Hz, 1 H) 6,88 (q, J=6.61 Hz, 1 H) 7.27 (d, J=7.32 Hz, 1 H) 7.35 - 7.41 (m, 1 H) 7.41 - 7.51 (m, 3 H) 7.77 (dd, J=8.27, 2.12 Hz, 1 H) 7.88 - 7.97 (m, 2 H)k !H NMR (400 MHz, MeOH-d4): 6 ppm 1.57 (d, J-3.37 Hz, 4 H) 2.04 (dd, J=13.40, 7.20 Hz, 1 H) 2,30 (dd, J=13.35, 9.20 Hz, 1 H) 2,40 (s, 3 H) 2,63 (t, J=7.61 Hz, 2 H) 2.96 (t, J=7.57 Hz, 2 H) 3.03 - 3.26 (m, 2 H) 3.39 - 3.76 (m, 4 H) 4.07 (dd, J=9,03, 7.32 Hz, 1 H) 5.78 (s, 1 H) 6.41 (d, J=2.29 Hz, 1 H) 6.86 (q, J=6.54 Hz, 1 H) 7.34 (d, J=8.25 Hz, 2 H) 7.46 (d, J=8.30 Hz, 1 H) 7.52 (d, J=8.25 Hz, 2 H) 7.76 (dd, J=8.27, 2,12 Hz, 1 H) 7.89 - 7.92 (m, 2 H)
1 ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.45 - 1.65 (m, 4 H) 2.00 - 2.09 (m, 1 H) 2.30 (dd, J=13.40, 9.25 Hz, 1 H) 2.40 (s, 6 H) 3.03 - 3.27 (m, 2 H) 3.39 - 3.76 (m, 4 H) 4.07 (dd, J=9.10, 7.25 Hz, 1 H), 4.67 (s, 2 H) 5,79 (s, 1 H) 6.41 (d, J=2.25 Hz, 1 H) 6.86 (q, J=6.64 Hz, 1 H) 7.36 - 7.53 (m, 4 H) 7.77 (dd, J=8,30, 2, 15 Hz, 1 H) 7.91 (d, J=2.44 Hz, 2 H)
m *H NMR (400 MHz, MeOH-d4) : δ ppm 1.46 - 1.69 (m, 4 H) 2.00 - 2.10 (m, 1 H) 2.30 (dd, J=I 3.45, 9.25 Hz, 1 H) 2.37 (s, 3 H) 2.40 (s, 3 H) 3.03 - 3,27 (m, 2 H) 3.39 - 3.76 (m, 4 H) 4.07 (dd, J=9.13, 7.22 Hz, 1 H) 4.70 (s, 2 H) 5,78 (s, 1 H) 6.41 (d, J=2.25 Hz, 1 H) 6.85 (q, J-6.57 Hz, 1 H) 7.26 (d, J=7.91 Hz, 1 H) 7.43 (dd, J=7.81, 1.95 Hz, 1 H) 7.47 (d, J=8.30 Hz, I H) 7.64 (d, J=1.81 Hz, 1 H) 7.79 (dd, J=8.27, 2.12 Hz, 1 H) 7.91 (d, J=2.29 Hz, 1 H) 7,94 (s, 1 H)
n ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 7.2 Hz, 1H), 1.56 (d, J = 6.3 Hz, 4H), 2.03 (d, J - 12.8 Hz, 1H), 2.30 (d, J = 12.4 Hz, 1H), 2.39 (s, 3H), 3.09 (d, J = 11.5 Hz, 1H), 3.22 (d, J = 1 1.7 Hz, 1H), 3.47 (t, J = 18.6 Hz, 2H), 3.63 (s, 2H), 4,07 (s, 1H), 4.64 (s, 1H), 5.78 (s, 1H), 6,41 (d, J = 2.1 Hz, 1H), 6.87 (q, J - 6.5 Hz, 1H), 7.44 (m, 4H), 7.59 (d, J = 7.4 Hz, 2H), 7.64 (s, 1H), 7.77 (m, 1H), 7.91 (m, 2H)
o Ή NMR (400 MHz, MeOH-d4): δ ppm 1.30 (d, J = 18.0 Hz, 1H), 1.57 (d, J = 6.1 Hz, 4H), 2.04 (dd, J = 13.9, 6.4 Hz, 1H), 2.30 (dd, J = 13.5, 8.4 Hz, 1H), 2.39 (s, 3H), 3.1 1 (d, J = 1 1.6 Hz, 1H), 3.23 (d, J = 11 ,4 Hz, 1H), 3.48 (dq, J = 21.6, 7.6, 6.8 Hz, 2H), 3.64 (dd, J = 13.8, 6.9 Hz, 2H), 4,08 (m, 1H), 4.87 (s, 12H), 5.78 (s, 1H), 6.41 (d, J = 2.0 Hz, 1H), 6.91 (q, J = 6.6 Hz, 1H), 7.36 (m, 2H), 7.50 (t, J = 9,3 Hz, 2H), 7,74 (dd, J = 8.3, 2.2 Hz,
Figure imgf000153_0001
Example 20: (S)-8-(2-amino-6-((R)-l-(21-(ethoxycarbonyl)-4-(3-methyl-lH-pyrazol-l-yl)- [l,l'-biphenyl]-3-yl)-2,2,2-trifluoiOethoxy)pyrimitlin-4-yl)-2,8-diazaspiro[4.5](lecane-3- carboxylic acid
Figure imgf000153_0002
The title compound was made using the procedure described for (S)-8-(2-amino-6-((R)-l -(3'- (ethoxycarbonyl)-3-(3-methyl-lH-pyrazol- l-yl)-[l ,r-biphenyl]-4-yl)-2,2,2- irifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid (Example 5a) starting with (S)-8-(2-amino-6-((R)-l-(5-bromo-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- tritluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid. Hi NMR (400 MHz, MeOH-d4): δ ppm 0.89 (t, J=7.15 Hz, 3 H) 1.60 (t, J=5.54 Hz, 4 H) 2.06 (dd, J=13.50, 7.25 Hz, 1 H) 2.33 (dd, J=13.42, 9.27 Hz, 1 H) 2.40 (s, 3 H) 3.08 - 3.28 (m, 2 H) 3.39 - 3.73 (m, 4 H) 3.74 - 3.98 (m, 2 H) 4.08 (dd, J=9.08, 7.32 Hz, 1 H) 5.74 (s, 1 H) 6.42 (d, J=2.34 Hz, 1 H) 6.88 (q, J=6.75 Hz, 1 H) 7.38 (dd, J=7.71, 0.93 Hz, 1 H) 7.45 - 7.56 (m, 4 H) 7.58 - 7.65 (m, 1 H) 7.82 (dd, J=7.69, 1.20 Hz, 1 H) 7.95 (d, J=2.34 Hz, 1 H). LCMS (MH+): 680.
Example 21: (S)-8-(2-amino-6-((R)-l-(4'-(ethoxycarbonyl)-4-(3-methyl-lH-pyrazol-l-yl)- [1 ,-biphenyI]-3-yl)-2,2,2-trifluoroethoxy)pyriinidin-4-yl)-2,8-diazaspiroE4.5](lecane-3- carboxylic acid
Figure imgf000154_0001
The title compound was made using the procedure described for (S)-8-(2-amino-6-((R)-l-(3'- (ethoxycai'bonyl)-3-(3-methyl- 1 H-pyrazol-1 -yl)-[l , 1 '-biphenyl]-4-yl)-2,2,2- trifluoi ethoxy)pynmidin-4-yl)-2,8-diazaspiro[4,5]decane-3-carboxylic acid (Example 5) starting with (S)-8-(2-amino-6-((R)-l-(5-bromo-2-(3-methyl-lH-pyrazol-l -yl)phenyl)-2,2,2- tiifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid.
1H NMR (400 MHz, MeOH-d4): δ ppm 1.41 (t, J=7.15 Hz, 3 H) 1.58 (br. s., 4 H) 2.05 (dd, J=13.50, 7.15 Hz, II) 2.30 (dd, J=13.42, 9.18 Hz, 1 H) 2.40 (s, 3 H) 3.03 - 3.28 (m, 2 H) 3.37 - 3.76 (m, 4 H) 4.07 (dd, J=9.13, 7.22 Hz, 1 H) 4.39 (q, J=7.13 Hz, 2 H) 5.78 (s, 1 H) 6.42 (d, J=2.25 Hz, 1 H) 6.86 - 7.01 (m, 1 II) 7.53 (d, J=8.30 Hz, 1 H) 7.66 - 7.77 (m, 2 H) 7.84 (dd, J=8.30, 2.20 Hz, 1 H) 7.94 (d, J=2.29 Hz, 1 H) 7.99 (d, J=1.51 Hz, 1 H) 8.06 - 8.17 (m, 2 H). LCMS (MH+): 680. Example 22a: (S)-8-(2-ainino-6-((R)-l-(5-ethyI-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifliioroethoxy)pyrimidin-4- -2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000155_0001
Step I: (S)-Ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-l-(2-(3-methyl- lH-pyrazol-l-yl)-5- vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-cai"boxylate (100 mg, 0.171 mmol) in MeOH (2 mL) was hydrogenated via an H-Cube apparatus using a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 mL/min at RT. The catalyst was filtered and the filtrate was concentrated in vacuo. The resisdue was lyophilized from 1 :1 H20:CH3CN to provide (S)-ethyl 8-(2-amino-6-((R)-l-(5-ethyl-2-(3-methyl-lH-pyrazoI-l-yl)phenyl)-2,2,2- trifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a white solid which was used directly in the next step.
Step 2; Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-l-(5-ethyl-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate using the LiOH general method provided the title compound as a white solid.
Using the same generic scheme below, the following examples of Table 8a can be prepared as described above for (S)-8-(2-amino-6-((R)-l-(5-ethyl-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2)2,2-trifluoiOethoxy)pyiimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxyiic acid (Example 22a).
Figure imgf000156_0001
Figure imgf000156_0002
Table 8b.
NMR Data for Compounds of Table 8a
Ex. |NMR
No.1 22a Ή NMR (400 MHz, MeOH-d4): 8 ppm 1.24 (t, J=7.59 Hz, 3 H) 1.57 (m, 4 H) 2.06 (dd, J=13.42, 7.13 Hz, 1 H) 2.32 (dd, J=13.45, 9.20 Hz, 1 H) 2.37 (s, 3 H) 2.72 (q, J=7.61 Hz, 2 H) 3,18 (m, 2 H) 3.57 (m, 4 H) 4.08 (dd, J=9.13, 7.17 Hz, 1 H) 5.74 (s, 1 H) 6.36 (d, J=2.34 Hz, 1 H) 6.71 (q, J=6.65 Hz, 1 H) 7.31 (m, 1 H) 7.39 (m, 1 H) 7.56 (s, 1 H) 7.82 (d, J-2.29 Hz, 1 H)
22b Ή NMR (400 MHz, MeOH-d4): δ ppm 0.91 (t, J=7.35 Hz, 2 H) 1.62 (m, 6 H) 2.06 (dd, J=13.52, 7.17 Hz, 1 H) 2.31 (dd, J=13.45, 9.25 Hz, 1 H) 2,37 (s, 3 H) 2.66 (t, J=7.52 Hz, 2 H) 3.18 (m, 2 H) 3,56 (m, 4 H) 4.08 (dd, J=9.13, 7.17 Hz, 1 H) 5.74 (s, 1 H) 6.36 (d, J=2,29 Hz, 1 H) 6.70 (q, J=6.70 Hz, 1 H) 7.31 (m, 1 H) 7.37 (m, 1 H) 7.53 (s, 1 H) 7.82 (d, J=2,29 Hz, 1 H)
22c Ή NMR (400 MHz, MeOH-d4): δ ppm 0.92 (t, J=7.37 Hz, 2 H) 1.32 (dq, J=T4.94, 7.38 Hz, 2 H) 1.60 (m, 6 H) 2.06 (dd, J=13.37, 7.22 Hz, 1 H) 2.31 (dd, 1=13.45, 9.25 Hz, 1 H) 2.37 (s, 3 H) 2.69 (t, J=7.59 Hz, 2 H) 3.18 (m, 2 H) 3.58 (m, 4 H) 4.08 (dd, J=9.20, 7.25 Hz, 1 H) 5.75 (s, 1 H) 6.36 (d, J=2.15 Hz, 1 H) 6.69 (q, J=6.62 Hz, 1 H) 7.30 (m, 1 H) 7.37 (m, 1 H) 7.53 (s, 1 H) 7.82 (d, J=2.29 Hz, 1 H)
Example 23: (S)-8-(2-Amino-6-((R)-l-(5-(ethoxycarbonyl)-2-(3-metliyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyriinidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxyIic acid
Figure imgf000157_0001
Step 1: To a solution of (S)-8-(2-amino-6-((R)-l-(5-bi mo-2-(3-methyl-lH-pyi-azol-l- yl)phenyl)-2>2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid (product of Step 3, Example 10m) (180 mg, 0.24 mmol) in ethanol (2 mL) was added Pd(PPh3)2Cl2 (34 mg, 0.048 mmol), KHC03 (242 mg, 2.4 mmol). A balloon of CO was fitted and the reaction mixture was heated to 80 °C for 20 h, then cooled to RT. The reaction was quenched with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO<i, filtered, and concentrated in vacuo.
Purification by normal phase silica gel column (CH2Cl2/MeOH/AcOH) provided (S)-8-(2-amino- 6-((R)-l-(5-(ethoxycarbonyl)-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane~3-carboxylic acid as an off- white solid. Step 2; N-CBZ Deprotection of (S)-8-(2-amino-6-((R)-l-(5-(ethoxycarbonyi)-2-(3-methyl-lH- pyrazol-l-yl)plienyl)-2,2,2-tvifluoiOethoxy) pyrimidin-4-yI)-2-((benzyloxy)carbonyl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid was accomplished via Method A to provide the title compound as an off-white solid.
'H MR (400 MHz, DMSO-d6): δ ppm 1.34 (t, J=7,10 Hz, 3 H) 1.51 - 1.71 (m, 4 H) 1.90 (dd, J=13.28, 9.18 Hz, 1 H) 2.26 - 2.40 (m, 4 H) 3.13 (br. s., 2 H) 3.66 (br. s., 4 H) 4.29 - 4.52 (m, 4 H) 6.07 (s, 1 H) 6.47 (d, J=2.39 Hz, 1 H) 7.48 (d, J=6.05 Hz, 1 H) 7.72 (d, J=8.40 Hz, 1 H) 8.15 (dd, J=8.40, 1.95 Hz, 1 H) 8.19 - 8.29 (m, 2 H) 8.96 (d, J=5.56 Hz, 1 H) 10.36 (d, J-4.49 Hz, 1 H). LCMS (MH+): 604.
Example 24: (S)-8-(2-Amino-6-((R)-l-(5-carboxy-2-(3-methyl-lH-pyrazol-l-yl)phenyl)- 2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000158_0001
Hydrolysis of (S)-8-(2-amino-6-((R)-l -(5-(ethoxycarbonyl)-2-(3-methyl- 1 H-pyiazol-1 - yl)phenyl)-2}2J2-tiifliioi ethoxy)pyrimidin-4-yl)-2>8-diazaspiro[4.5]decane-3-carboxylic acid (Example 23) using the LiOH general method provides the title compound as a white solid. !H NMR (400 MHz, DMSO-d6): δ ppm 1.45 - 1.65 (m, 4 H) 1,83 - 1.95 (m, 1 H) 2.26 - 2.38 (m, 4 H) 3.12 (br. s., 2 H) 3.61 (br. s„ 4 H) 4.36 - 4,51 (m, 1 H) 5.93 (br. s.5 1 H) 6.46 (d, J=2.39 Hz, 1 H) 7.40 (m, J=5.80 Hz, 1 H) 7.67 (d, J=8.35 Hz, 1 H) 8.11 (dd, J=8.35, 1.95 Hz, 1 H) 8.21 (d, J=2.39 Hz, 1 H) 8.25 (s, 1 H) 8.93 (m, J=4.40 Hz, 1 H) 10.09 (br. s., 1 H). LCMS (MH+): 576.
Example 25: (S)-8-(2-Amino-6-((R)-2,2,2-irifluoro-l-(4-(liydroxymethyl)-2-(3-methyl-lH- pyrazol-l-yl)phenyI)ethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-cai,boxylic acid
Figure imgf000159_0001
Step 1: To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l-(4-biOmo-2-(3-methyI-lH- pyrazol-l-yl)phenyl)-2,2,2-tiifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3- dicarboxylate (386 mg, 0.50 mmol) in DMF (10 mL) and Et3N (0.35 mL, 2.5 mmol) was added (n-octyl)3SiH (368 mg, 1 ,0 mmol). The mixture was degassed under 1 atm of CO balloon and PdCl2(PPh3)2 (72 mg, 0.10 mmol) was added, then degassed again with 1 atm of CO, and heated to 80 °C for 12 h. The reaction was cooled to RT and concentrated in vacuo. The residue was diluted with water then extracted with EtOAc. The combined organic layers were dried over Na2S04) filtered, and concentrated in vacuo. Normal phase column chiOmatography on silica gel (EtOAc / heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifiuoiO- 1 -(4-formyl- 2-(3 -methyl - 1 H-py razol- 1 -y l)plieny l)ethoxy)pyri m idin- 4-y 1) -2 , 8 -diazaspiro [4.5] decane-2,3 - dicarboxylate as a light yellow solid contaminated with about 25% of (S)-2-benzyl 3-ethyl 8-(2- amino-6-((R)-2J2,2-trifluoiO- 1 -(2-(3-methyl- IH-pyrazol- 1 -yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as by-product. The mixture was used directly in the next step.
Step 2 To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifiuoiO-l-(4-formyl-2-(3- methyl-lH-pyrazol-l -yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-2,3- dicarboxylate (36 mg, 0.05 mmol) in dichloroethane (2 mL) was added NaCNBH3 (1M in THF, 1 mL, 0.5 mmol), followed by a few drops of HO Ac. The mixture was stirred at RT for 3 h then concentrated in vacuo. The residue was dissolved in MeOH and purified on reverse phase HPLC (MeOH/H20/HOAc) to provide (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4- (hydroxymethyl)-2-(3-methyl-lH-pyrazol-l -yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-2,3-dicarboxylate as a sticky solid that was used without further purification. Step 3\ N-CBZ Deprotection was accomplished via Method B to provide (S)-ethyl 8-(2-amino-6- ((R)-2,2;2-trifluoiO-l-(4-(hydroxymethyl)-2-(3-methyl-lH-pyrazol-l- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspitO[4.5]decane-3-carboxylate as a white solid. Step 4: Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro- 1 -(4-(hydroxymethyi)-2-(3- methyl-lH-pyrazol-l-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provided the title compound as a white solid.
Ή NMR (400 MHz, MeOH-d4): δ ppm 1.57 (t, J=5.15 Hz, 4 H) 1.91 - 2.12 (m, 7 H) 2.30 (dd, J=13.23, 9.42 Hz, 1 H) 2.36 (s, 3 II) 3.07 - 3.26 (m, 2 H) 3.39 - 3.54 (m, 2 H) 3.58 - 3.70 (m, 2 H) 3.99 - 4.13 (m, 1 H) 4.65 (s, 2 H) 5.71 (s, 1 H) 6.37 (d, J=2.34 Hz, 1 H) 6.74 (q, J=6.65 Hz, 1 H) 7.39 (s, 1 H) 7.45 (d, J=8.20 Hz, 1 H) 7.68 (d, J=8.10 Hz, 1 H) 7.84 (d, J=2.34 Hz, 1 H). LCMS (MH+): 562. Example 26: (S)-8-(2-amino-6-((R)-l-(4-((dimethylamino)methy])-2-(3-methyl-lH-pyrazol- l-yl)plienyl)-2,2,2-trifluoroethoxy)pyriniidin-4-yl)-2,8-(liazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000160_0001
Step 1: To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4-formyl-2-(3- methyl-lH-pyrazol-l-yl)phenyl)ethoxy)pyiimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3- dicarboxylate (166 mg, 0,23 mmol, see Ex. 25) in dichloro ethane (4 mL) and HO Ac (10 nig) was added NaBH(OAc (242 mg, 1.15 mmol) and Me2NH (2M in THF, 0.58 mL, 1.15 mmol). The reaction mixture was stirred at RT for 20 h then concentrated in vacuo. The residue was dissolved in MeOH (1 mL) and purified by reverse phase HPLC (MeOH/H20/HOAc) to provide (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l -(4-((dimethylamino) methyl)-2- (3 -methyl- lH-pyrazol- l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-2,3-dicarboxylate as a white solid.
Step 2: N-CBZ Deprotection was accomplished via Method A to provide (S)-ethyl 8-(2-amino-6- ((R)- 1 -(4-((dimethylamino)methyl)-2-(3-methyI- 1 H-pyrazol- 1 -yl)phenyl)-2}2,2- tnfluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a white solid.
Step 3; Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-l-(4-((dimethylamino)methyl)-2-(3-methyl- lH-pyrazol-l-yl)phenyl)-2,2;2-trifluoiOethoxy)pyrimidin"4-yl)-2,8-diazaspiiO[4.5]decane-3- carboxylate using the LiOH general method provided the title compound as a white solid,
¾ NMR (400 MHz, MeOH-d4): δ ppm 1.66 - 1.81 (m, 4 H) 2.10 (dd, J=13.62, 8.54 Hz, 1 H) 2.38 (s, 3 H) 2.49 (dd, J=13.62, 8,88 Hz, 1 H) 2.88 (s, 3 H) 2,90 (s, 3 H) 3.58 - 3.90 (m, 4 H) 4.37 - 4.49 (m, 2 H) 4.56 (t, J=8.69 Hz, 1 H) 6.37 (br. s„ 1 H) 6.43 (d, J=2.34 Hz, 1 H) 7.06 - 7.12 (m, 1 H) 7,71 - 7.78 (m, 2 H) 7.85 (d, J=8.10 Hz, 1 H) 7.98 (d, J 2.39 Hz, 1 H). LCMS (MH+): 589.
Example 27: (S)-8-(6-(( )-l-(4-Bromo-2-(3-methyI-lH-pyrazol-l-yl)phenyl)-2,2)2- trifluoroethoxj ^-inethylpyrimidin^-ylJ- jS-diazaspiro^.Sjdecane-S-carboxylic acid
Figure imgf000161_0001
Step 1: To a solution of l(^)-l-[4-bromo-2-(3-methyl-lH-pyrazol-l-yl)phenyl]-2,2,2- trifluoioethanol (15.7 g, 46.3 mmol, Intermediate 1) in dioxane (200 mL) was added 4,6- dichloiO-2-methylpyrimidine (30,6 g, 51 mmol) and CS2CO3 (61.2 g, 187 mmol). The reaction mixture was heated to 80 °C for 30 h, then cooled to RT, and filtered. The residue was concentrated in vacuo and purified by normal phase column chromatography on silica gel (CH2C12 /heptane) to provide (R)-4-(l -(4-bromo-2-(3-methyl-lH-pyrazol-l-yl)phenyI)-2,2,2- trifluoroethoxy)-6-chloiO-2-methylpyrimidine as a white solid.
Step 2; To a solution of (R)-4-(l-(4-bromo-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)-6~chloiO-2-methylpyrimidine (21 g) in dioxane (200 ml) was added (S)-2- benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (15 g) and Na2C03 (14 g). The reaction was heated to 90 °C for 48 h, then cooled to RT, filtered, and concentrated in vacuo. Purification of the residue on normal phase column chromatography on silica gel (EtOAc /heptane) provided (S)-2-benzyl 3-ethyl 8-(6-((R)-l-(4-bromo-2-(3 -methyl- lH-pyrazol-1 - yl)phenyl)-2,2i2-trifluoi ethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-2,3- dicarboxylate as an off-white solid.
Step 4: N-CBZ Deprotection was accomplished via Method A to provide (S)-ethyl 8-(6-((R)-i~ (4-bromo-2-(3-methyl- 1 H-pyrazol- 1 -yl)phenyl)-2,2,2-ti'ifluoroethoxy)-2-methylpyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate an off-white solid.
Step 5: Hydrolysis of (S)-ethyl 8-(6-((R)-l-(4-bromo-2-(3-methyl-lH-pyrazol-l -yl)phenyl)- 2,2!2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-258-diazaspiro[4.5]decane-3-carboxyIate using the LiOH general method provided the title compound as an off-white solid.
'H NMR (400 MHz, MeOH-d4): δ ppm 1.64 (br. s„ 4 H) 2.10 (d, J=7.03 Hz, 1 H) 2.28 (s, 3 H) 2.35 (dd, J=13.37, .27 Hz, 1 H) 2.39 (s, 3 H) 3.10 - 3.20 (m, 1 H) 3.28 (d, J=11.91 Hz, 1 H) 3.45 - 3.67 (m, 2 H) 3.75 (br. s.} 2 H) 4.10 (dd, J=8.98, 7.22 Hz, 1 H) 6.17 (s, 1 H) 6.43 (d, J=2.15 Hz, 1 H) 7.01 (d, J=6.44 Hz, 1 H) 7.58 - 7.75 (m, 3 H) 8.03 (d, J=2.15 Hz, 1 H). LCMS (MH+); 609.
Example 28: (S)-8-(6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)-2-methyl pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000163_0001
The title compound was prepared as described above for (S)-8-(6-(( )-l-(4-biOino-2-(3-methyl- lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)-2-methylpydmidin-4-yl)-2,8- diazasph'o[4.5]decane-3-carboxylic acid (byr replacing l(i?)-l-[4-bromo-2-(3-methyl-lH- pyrazol-l-yl)phenyl]-2,2,2-trifluoi ethanol with l(i?)-l-[4-chloro~2-(3-methyl-lH-pyrazol-l- yl)phenyl]-2,2,2-trifluoroethanolJ Intermediate 3) and obtained as an off-white solid,
¾ NMR (400 MHz, DMSO-d6): δ ppm 1,34 - 1.54 (m, 4 H) 1.82 (dd, J=13.01, 6.76 Hz, 1 H) 1.99 - 2.08 (m, 1 H) 2, 1 1 (s, 3 H) 2.30 (s, 3 H) 2.92 (d, J=l 1.52 Hz, 1 H) 3.06 (d, J=l 1.52 Hz, 1 H) 3.42 - 3.65 (m, 4 H) 3.70 (dd, J=8.91, 7.00 Hz, 1 H) 6.15 (s, 1 H) 6.42 (s, 1 H) 7.43 (q, J=6,93 Hz, 1 H) 7.54 - 7.61 (m, 1 H) 7.64 (d, 3=2, 10 Hz, 1 H) 7.70 (d, J=8.44 Hz, 1 H) 8.19 (d, J=2.39 Hz, i H) 8.70 (br. s., 1 H). LC S (MH+): 565.
General biaryl coupling (Suzuki procedures
Biaryl coup! ing method A
Step 1; To a mixture of (S)-2-((benzyloxy)carbonyl)-8-(6-((R)-l-(4-bromo-2-(3-methyl- lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoiOethoxy)-2-methylpyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid (product of Step 3, Example 10m) (150 mg, 0.2 mmol), an arylboronic acid (0.4 mmol), Pd(N,N-dimethyl p-alaninate)2 (3.42 mg, 0.01 mmol), and
K3PO4 (128 mg, 0.6 mmol) were added water (3.0 mL) and EtOH (3.0 mL). The mixture was stirred at 50 °C for 12 h. The reaction was then cooled to RT, diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuo. The target biaryl compounds were purified by normal phase silica gel column
(CH2Cl2:MeOH).
Step 2; Subsequent N-CBZ deprotection via method A afforded the final target spirocyclic amino acids. Bi r l coupling method B
Step h To a mixture of (S)-2-((benzyloxy)carbonyl)-8-(6-((R)-l-(4-bromo-2-(3-methyl- lH-pyrazol-l -yl)phenyl)-2,2,2-trifluoi ethoxy)-2-methylpyiimidin-4-yl)-2,8- diazaspiiO[4.5]decane-3-carboxylic acid (product of Step 3, Example 10m) (150 mg, 0.2 mmol), an arylboronic acid (0.4 mmol), Pd(OAc)2 · (l,l,3,3-tetramethyl-2-N-butylguanidine)2 (5.7 mg, 0.01 mmol), and 2C03 (83.5 mg, 0.61 mmol) was added water (1.0 mL) and dioxane (3.0 mL). The reaction mixture was stirred at 44°C for 24 h. The reaction mixture was then cooled to RT, diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuo. The target biaryl compounds were purified by normal phase silica gel column (CH2Cb:MeOH).
Step 2 Subsequent N-CBZ deprotection via method A afforded the final target spirocyclic amino acids.
Using the generic scheme below and employing the biaryl coupling method A, the following examples of Table 9 were prepared.
Figure imgf000164_0001
Table 9.
Figure imgf000165_0001
Ex. No. Cy CAS Name LCMS (MH+)
29a (S)-8-(2-methyl-6-((R)-252,2-tiifluoro-l-(4-(2- 638
methoxypyridin-4-yl)-2-(3-methyl-lH-pyrazol-l- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3 -carboxyl ic acid
29b (S)-8-(2-methyl-6-((R)-252,2-trifluoiO-l-(3-(3- 686
methyl-lH-pyrazol-l-yl)-4'-(methylsulfonyl)- [l}r-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5] dec ane -3 - carboxyl ic acid
29c (S)-8-(6-((R)-l-(3',4'-difluoiO-3-(3-methyl-lH- 645
pyrazol- 1 -yl)-[l , 1 '-bi henylH-yl)^^- trifluoi ethoxy)-2-methylpyrimidin-4-yl)-2,8- diazaspii [4.5]decane-3-carboxylic acid
29(1 (S)-8-(6-((R)-l-(3*,4'-dimethyl-3-(3-methyl-lH- 635
pyrazol- 1 -yl)-[l , 1 ,-biphenyl]-4-yl)-2,2J2- trifluoroethoxy)-2-methylpynmidin-4-yl)-2}8- diazaspii [4.5]decane-3-carboxylic acid
29e (S)-8-(6-((R)- 1 -(3'-(ethoxycarbonyl)-3-(3-methyl- 680
lH-pyrazol-l-yl)-[l,r-bip enyl]-4-yl)-2,2,2- tiifluoiOethoxy)-2-methylpyrimidin-4-yl)-258- diazaspiio[4.5]decaiie-3-carboxylic acid
29f (S)-8-(2-methyl-6-((R)-2;2,2-trifluoiO- 1 -(4-(6- 639
methoxypyridin-3-yl)-2-(3-methyl-lH-pyrazol-l- yl)p enyi)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4.5] dec ane-3 - carboxyl ic acid
29g (S)-8-(2-methyl-6-((R)~252,2-trifluoiO-l-(4-(2- 640
methoxypyrimidin-5-yl)-2-(3-methyl-lH-pyrazol- 1 -yl)phenyl)ethoxy)pyrimid i n- 4-y l)-2, 8 - diazaspiro[4.5]decaiie-3-cai*boxylic acid
29h (S)-8-(6-((R)-l-(2, }4!-dimethoxy-3-(3-methyl-lH- 668
pyrazol-l-yl)-[l>r-biphenyl]-4-yl)-2,2!2- ti,ifluoi'oethoxy)-2-methylpyriinidin-4-yl)-2J8- diazaspii [4.5]decane-3-cai'boxylic acid 29i (S)-8-(6-((R)-l-(4'-(ethoxycarbonyl)-3-(3-methyl- 679
1 H-pyrazol- 1 -yl)-[ 1 , 1 '-biphenyl]-4-yl)-2,2,2- ti'ifluoroetlioxy)-2-methy Ipyrimidin- 4-yl) -2,8- diazaspiro[4.5]decane-3-carboxylic acid
29j (S)-8-(6-((R)-l-(4,-(dimeihylcarbamoyl)-3-(3- 678 methyl- 1 H-pyrazol- 1 -yl)-[l , 1 '-biphenyl]-4-yl)- 2,2,2-trifluoi ethoxy)-2-metl ylpyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-cai'boxylic acid
29k (S)-8-(2-methyl-6-((R)-2,2,2-trif!uoiO-l -(4-(2- 639
Yv methoxypyridin-3 -yl)-2-(3 -methyl- 1 H-pyrazol- 1- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspii [4.5]decane-3-carboxylic acid
291 (S)-8-(2-methyl-6-((R)-2,2J2-trifliioro-l-(3'- 655.6 fluoio-4'-methoxy-3-(3-methyl-lH-pyrazol-l-yl)- [1 , -biphenyi]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4 , 5]decane-3 -carboxy 1 ic acid
29m 1 (S)-8-(6-((R)-i-(3'-(dimethylcarbamoyl)-3-(3- 679 methyl-1 H-pyrazol- 1 -yl)-[l 5l'-biphenyl]-4-yl)- 2,2,2 -trifluoroethoxy)-2-methylpyrimidin-4-yl)-
0 2,8-diazaspiro[4.5]decane-3-carboxylic acid
Using the generic scheme above with the biaryi coupling method B, the following examples of Table 10 were prepared.
Table 10.
Figure imgf000166_0001
Figure imgf000166_0002
Figure imgf000167_0001
29aa (S)-8-(2-methyl-6-((R)-2,2,2-trifluoi - 1 -(3'-methoxy- 638
3 -(3 -methyl- 1 H-pyrazol- 1 -yl)-[l , 1 '-biphenylj-4- yl)emoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- 3-carboxylic acid
29ab (S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-l-(2-(3-methyl- 608
l H-pyrazol-l-yl)-4-(pyridin-4- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiiO[4.5]decane-3-carboxylic acid
Example 30a: 8-(6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazoH-yl)phenyl)-2,2,2- trifluoroethoxy)-2-pheno ane-3-carboxyIic acid
Figure imgf000168_0001
Step J: To a solution of (7?)-l -[4-chloro-2-(3-methylpyi'azol-l-yl)phenyl]-2,2,2-trifluoiOethanol (5.00 g, 17.2 mmol) and 4,6-dichloro-2-(methylthio)pyrimidine (3.36 g, 17.2 mmol) in dioxane (250 mL) was added Cs2C03 (16,8 g, 51.6 mmol). The reaction mixture was then heated to 70 °C for 90 h, then cooled to RT. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. Purification on a 120 g Isco RediSep silica cartridge
(EtOAc : heptane) provided 4- chl oro -6-[(R)- 1 - [4 -ch loro-2 -(3 -methylpyrazol - 1 -yl)pheny 1] -2,2,2- tdfluoroethoxy]-2-methylsulfanylpyrimidine as a white solid.
Step 2: To a solution of 4-chioi -6-[(i?)-l -[4-chloro-2-(3-methylpyrazol-l-yl)phenyl]-2,2,2- tdfluoroethoxy]-2-methylsulfanylpyrimidine (4 g, 8.95 mmol) in Ο½02 (200 mL) was added w-CPBA (4.2 g of a 77% (w/w) source, 18,8 mmol) and the reaction was stirred at RT for 15 h. The reaction was then diluted with saturated NaHC03, and extracted with CH2C12. The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. Purification on a 120 g Isco RediSep silica cartridge (EtOAc:heptane) provided 4- chloro-6-[(l Ji)- 1 -[4-chloro-2-(3-methylpyrazol-l -yl)phenyl]-2,2,2-trifluoroethoxy]-2- methylsulfonylpyrimidine as an off-white solid.
Step 3 To a solution of 4-chloi -6-[(li?)-l-[4-chloiO-2-(3-methylpyrazol-l-yl)p enyl]-2,2,2- tiifluoiOethoxy]-2-methylsulfonylpyrimidine (2.49 g, 5.17 mmol) in dioxane (100 mL) was added 2-benzyl 3 -ethyl 2,8~diazaspitO[4.5]decane-253-dicarboxylate (1.8 g, 5.2 mmol), Cs2C03 (5.06 g, 15,5 mmol), and the reaction mixture was heated to 100 °C for 1.5 h. The reaction mixture was cooled to RT, quenched with brine, and extracted with EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuo. Purification on a 120 g Isco RediSep silica cartridge (EtOAc:heptane ) provided (S)-2-benzyl 3-ethyl 8-(6-((R)-l - (4-chloro-2-(3-methyl-lfI-pyrazol-l-yl)phenyl)-252,2-trifluoiOethoxy)-2-(n etliylsulfonyl) pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid (1.3 g) in addition to (S)-2-benzyl 3-ethyl 8-(4-chloiO-6-((R)-l-(4-chloro-2-(3-methyl- lH-pyrazol-l-yl)phenyl)- 2J2,2-trifluoi'oethoxy)pyrimidin-2-yl)-2,8-diazaspiiO[4.5]decane-2,3-dicarboxylate.
Step 4: To a solution of 2-benzyl 3-ethyl 8-(6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifliwi ethoxy)-2-(methylsulfonyl)pyi½iidin-4-yl)-2,8-diazaspiro[4.5]decane- 2,3-dicarboxylate (2.10 g, 2.65 mmol) in 2: 1 THF:H20 (90 mL) was added LiOH (127 mg, 5,3 mmol), and the reaction was stirred at RT for 21 h, afer which additional LiOH (65 mg, 2.6 mmol) was added, and the reaction was stirred for 8 h longer. The reaction was then quenched with 1 N HCl to pH<l, and extracted with EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuo to provide 2-((benzyloxy)carbonyl)-8-(6-((R)-l -(4- chl oro -2-(3 -methyl- 1 H-pyrazol- 1 -yl)phenyl) -2,2,2 -trifluoro ethox y)-2- (methylsulfonyl)pyrimidin-4-yl)-2;8-diazaspiro[4.5]decane-3-carboxylic acid as an off-white solid which was used directly without further purification.
Step 5: To a solution of 2-((benzyloxy)carbonyl)-8-(6-((R)-l-(4-cliloro-2-(3-methyl-lH-pyrazoi- l-yl)phenyl)-2,2,2-trifluoiOethoxy)-2-(methylsulfonyl)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid (300 mg, 0.393 mmol) in 1,4-dioxane (10 mL) was added phenol (74 mg, 0.79 mmol), CS2CO3 (512 mg, 1.5 mmol), and the reaction was heated to 70 °C for 21 h. The reaction was then cooled to RT, diluted with water, acidified to pH<l with 1 N HO, and extracted with EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuo. Purification on a 50 g Isco Gold ediSep reverse phase silica cartridge (H20:HOAc : 99: 1 MeOH:HOAc 99: 1) provided 2-((benzyloxy)carbonyl)-8-(6- ((R)-l-(4-chloro-2-(3 -methyl- lH-pyrazol-l -yl)phenyl)-2,2,2-trifluoiOethoxy)-2- phenoxypyrimidin-4-yl)-2,8-diazaspiro[4,5]decane-3-carboxylic acid as an off-white solid.
Step 6: N-CBZ Deprotection was accomplished via Method B to provide the title compound as an off-white solid. Using the generic scheme below, the following examples of Table 1 la were prepared as described above for 8-(6-((R)-l-(4-chloi -2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)-2-phenoxypyrimidin-4-yl)-2,8-diazaspii [4,5]decane-3-carboxylic acid (Example 30a).
Figure imgf000170_0001
Table 11a.
Figure imgf000171_0001
Ex. R CAS Name LCMS (MH+) No.
30a 8-(6-((R)- 1 -(4-chloro-2-(3-methyl-l H-pyrazol- 1 - 644
yl)phenyl)-2}2,2-tnflxioi ethoxy)-2-phenoxypyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
30b 8-(6-((R)-l-(4-chloiO-2-(3-methyl-l H-pyrazol- 1 - 649
yl)phenyl)-2,2,2-trifluoiOethoxy)-2- (cyclohexyloxy)pyrimidin-4-yl)-2,8- diazaspiro [4.5] decane-3 -carboxy lie acid
Table lib.
NMR Data for Compounds of Table 11a
Ex. NMR
No.
30a Ή NMR (400 MHz, MeOH-d4): δ ppm 1.57 (br. s., 4 H), 2.00 - 2.31 (m, 2 H), 2.32 (s, 3 H), 3.06 - 3.28 (m, 2 H), 3.36 - 3.71 (m, 4 H), 4.07 (dd, J = 8.83, 7.37 Hz, 1 H), 6.11 (s, 1 H), 6.30 (d, J = 2.34 Hz, 1 H), 6.70 (q, J = 6.43 Hz, 1 H), 6.97 - 7.06 (m, 2 H), 7.10 - 7.20 (m, 1 H), 7.26 - 7.36 (m, 2 H), 7.47 (d, J = 2.15 Hz, 1 H), 7.54 (dd, J = 8.54, 2.15 Hz, 1 H), 7.71 (d, J = 8.54 Hz, 1 H), 7.86 (d, J = 2.39 Hz, 1 H).
30b !H NMR (400 MHz, MeOH-d4): δ ppm 1.16 - 1.95 (m, 14 H), 2.04 - 2.35 (m, 2 H), 2.36 (s, 3 H), 3.07 - 3.30 (m, 2 H), 3.43 - 3.82 (m, 4 H), 4.09 (dd, J = 8.86, 7.39 Hz, 1 H), 4.80 - 4.95 (m, 1 H), 5.98 (s, 1 H), 6.37 (d, J = 2.39 Hz, 1 H), 7.01 - 7.13 (m, 1 H), 7.45 - 7.55 (m, 2 H), 7.70 (d, J = 9.08 Hz, 1 H), 8.12 (d, J = 2.34 Hz, 1 H)
Example 31: 8-(6-((R)-l-(4-chloi'o-2-(3-methyHH-pyrazol-l-yl)pheiiyl)-2,2,2- trifluoroethoxy)-2-(cycIohexylamino)pyrimidin-4-yl)-2,8-diazaspiro[4,5]decane-3- carboxylic acid
Figure imgf000172_0001
The title compound was prepared as described above by replacing the alcohol in Step 5 of Example 30a with cyclohexyl amine. lH N R (400 MHz, MeOH-d4): δ ppm 0.99 - 1.95 (m, 14 H), 2.02 - 2.37 (m, 2 H), 2.38 (s, 3 H), 3,07 - 3.29 (m, 2 H), 3.41 - 3.77 (m, 5 H), 4.09 (dd, J= 9.10, 7.15 Hz, 1 H), 5.60 (s, 1 H), 6.39 (d, J= 2.39 Hz, 1 H), 6.87 - 7.21 (m, 1 H), 7.49 (dtd, J= 4.48, 2.26, 2.26, 2.12 Hz, 2 H), 7.70 (d, J= 9.03 Hz, 1 H), 7.87 (d, J= 2.34 Hz, 1 H). LC S (MH+): 650. Example 32: (S)-8-(6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroefhoxy)-2-(cyclobuianecarboxamido)pyrimidin-4-yl)-2,8-diazaspiro[4.5]tlecane-3- carboxylic acid
Figure imgf000172_0002
Step 1: To a solution of (S)-8-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid (product of Step 3, Example 10m) (300 mg, 0.412 mmol) in pyridine (1.0 mL) was added cyclobutanecarbonyl chloride (54 mg, 0.045 mmol). The reaction mixture was stirred at RT for 3 h, then diluted with EtOAc, and washed with 0,5 N HCl. The organic layer was dried over Na2S04} filtered, and concentrated in vacuo. Purification on a 40 g Isco RediSep silica cartridge (EtOAc/heptane) provides (S)-2-benzyl 3-ethyl 8-(6-((R)-l-(4- chloi -2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2-tiifluoiOethoxy)-2-(cyclobutanecarboxamido) pyrimidin-4-yl)~2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid,
Step 2: The title compound was prepared by the N-CBZ removal using the general method B to provide a white solid.
!H NMR (400 MHz, MeOH-d4): δ ppm 1.66 (d, J = 4,30 Hz, 4 H), 1.78 - 1.99 (m, 2 H), 2.03 - 2.38 (m, 6 H), 2.39 (s, 3 H), 3.12 - 3.32 (m, 2 H), 3.47 - 3.90 (m, 5 H), 4.10 (dd, J = 9.10, 7.20 Hz, 1 H), 6.03 (s, 1 H), 6.41 (d, J = 2.34 Hz, 1 H), 6.82 - 6.98 (m, 1 H), 7.45 - 7.57 (m, 2 H), 7.73 (d, J = 8.49 Hz, 1 H), 7.97 (d, J = 2.34 Hz, 1 H). LCMS (MH+): 649.
Example 33: (S)-8-(2-amino-6-((R)-l-(4-chloiO-2-(2-oxopyrrolidi-i-l-yl)phenyl)-2,2,2- trifluoroethoxy) pyrimidin-4- -2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000173_0001
The title compound was prepared as described for (S)-8-(2-amino-6-((R)- 1 -(4-chloro-2-(3- methyl-lH-pyrazol-l -yl)phenyl)-2i2,2-trifluoi ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid (Example lOd) starting with (R)-l-(5-chloro-2-(2,2,2- trifluoro- 1 -hydiOxyethyl)phenyl)pyrrolidin-2-one. 'H NMR (DMSO-d6): δ ppm 1.23 (m, 1H), 1 ,40 (m, 4H), 1.81 (dd, J = 13,2, 6.9 Hz, 1H)5 2.07 (m, 4H), 2.45 (d, J = 8.1 Hz, 2H), 2.91 (d, J = 11.5 Hz, 3H), 3.06 (d, J = 11.6 Hz, 1H), 3.47 (d, J = 6.9 Hz, 3H), 3.66 (m, 3H), 5.54 (s, 1H), 6.09 (s, 2H), 6.74 (q, J - 6.9 Hz, 1H), 7.55 (m, 3H). LCMS (MH+): 570. Example 34c: (S)-8-(2-amino-6-((R)-l-(5-chloro-[l,r-biphenyl]-2-yl)-2>2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxyIic acid 14 054202
Figure imgf000174_0001
Step 1: To a solution of (R)-l-(2-biOmo-4-chloiOphenyl)-2,2,2-trifluoiOethanol (Intermediate 43) (400 mg, 1.4 mmol) in dioxane (25 mL) was added 4,6-dichloiOpyrimidin-2-amine (1.1 g, 7 mmol) and CS2CO3 (1.3 g, 4 mmol). The mixture was heated for 24 h at 80 °C, The reaction was then cooled to RT and filtered. The solvent was removed in vacuo, then CH2CI2 and heptane was added. The solvent volume was reduced until a solid precipitated out. The solid was filtered and the procedure repeated several times to provide (R)-4-(i-(2-bromo-4-chiorophenyl)- 232,2-trifluoroethoxy)-6-chloi'opyrimidin-2-amine as a white solid. Step 2; To a solution of (R)-4-(l -(2-bromo-4-chIorophenyl)-2,2,2-trifluoroethoxy)-6- chloropyrimidin-2-amine (100 mg, 0.24 mmol, Step 1) in dioxane (5 mL) was added (S)-2- benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (100 mg, 0.29 mmol), and NaHCC (300 mg, 3.5 mmol). After 5 h, an additional amount of NaHCC (300 mg, 3.5 mmol) was added and the reaction mixture was heated to 90 °C for 36 h. The reaction was then cooled to RT and filtered. Purification by normal phase silica gel column (EtO Ac/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l-(2-biOmo-4-chloi phenyl)-2,2,2-trifluoiOethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Step 3: To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l-(2-bromo-4-chlorophenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2;8-diazaspiro[4.5]decane-2;3-dicarboxylate (100 mg, 0,13 mmol) in 10:1 dioxane:water (5 mL) was phenyl boronic acid (33 mg, 0.27 mmol), KHCO3 (27 mg, 0,3 mmol), and PdCl2(dppf)-CH2Cl2 (6 mg, 0.007 mmol). The reaction was heated to 100 °C for 15 h, cooled to RT, and concentrated in vacuo. The residue was diluted with water, and extracted with EtO Ac. The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtO Ac/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l-(5-chloiO-[l ,l'-biphenyl]-2-yl)-2,2,2- trifluoroethoxy}pynmidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.
Step 4: N-CBZ Deprotection was accomplished via method B to provide (S)-ethyl 8~(2-amiiio-6- ((R)-l-(5-chloro-[l ,l,-biphenyl]-2-yl)-2,2,2-tvifluoiOethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate an off-white solid.
Step 5: Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloi -[l)l'-biphenyl]-2-yl)-2,2J2- tiifluoi'oethoxy)pyrimidin-4-yl)-2}8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provided the title compound as an off-white solid as the zwitterionic form.
Example 34u: (S)-8-(2-amino-6-((R)-l-(5-chloro-3'-sulfamoyl-[l,l,-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyi imidin-4-yl)-2,8-diazaspii'o[4.5]decane~3-carboxylic acid
Figure imgf000175_0001
Step 1 ; To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R - 1 -(2-bromo-4-chlorophenyl)- 2,2)2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2}3-dicarboxylate (500 mg, 0.688 mmol) in 10: 1 dioxane:water (1 1 mL) was added 3-(4,4J5,5-tetramethyl- 1,3,2- dtoxaboiOlan-2-yl)benzenesulfonamide (1 5 mg, 0,7 mmol), KHCO3 (207 mg, 2.06 mmol), and PdCI2(dppf)-CH2Ch (56 mg, 0.069 mmol). The reaction was heated to 100 °C for 15 h, cooled to RT, and concentrated in vacuo. The residue was diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na2S0 , filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtO Ac/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l -(5-chloi -3'-sulfamoyl-[l,l'-biphenyl]-2-yl)-2J2,2- trifJuoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-2,3-dicarboxylate as an off-white solid. Step 2: N-CBZ Deprotection was accomplished via method B to provide (S)-ethyl 8-(2-amino-6- ((R 1 -(5-chloro-3'-sulfamoyl-[ 1 , 1 '-biphenyl]-2-yl)-2,2,2-trifliioiOethoxy)pyrimidin-4-yl)-2,8- diazaspiiO[4.5]decane-3-carboxylate as a white solid. Step 3: Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloi -3'-sulfamoyl-[l , l '-biphenyl]-2- yl)-2,2J2-trifluoroethoxy)pyrimidin-4-yl)-2J8-diazaspiiO[4.5]decane-3-carboxylate using the LiOH general method provided the title compound as an off-white solid.
Using the generic scheme below, the following examples of Table 12a can be prepared as described above for (S)-8-(2-amino-6-((R)-l-(5-chloiO-3'-sulfamoyl-[l ,l,-biphenyl]-2-yl)-2}2)2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid (Example 34u).
Figure imgf000176_0001
Table 12a.
Figure imgf000176_0002
Stereochemistry defined in in table below 2014/054202
Figure imgf000177_0001
Figure imgf000178_0001
u (S)-8-(2-amino-6-((R)-l -(5-chloi -3'-sulfamoyl-[l ,1'- 641 biphenyl]-2-yl)-2)2,2-trifIuoiOethoxy)pyrimidin-4- yl)-258-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000179_0001
v (S)-8-(2-amino-6-((R)-l -(5-chloro-3'-hydroxy-[l , 1 '- 578 biphenyl]-2-yl)-2,2,2-ti"ifluoi ethoxy)pyrimidin-4- y l)-2 , 8 -diazaspiro [4.5] dec ane -3 -car boxyl ί c aci d
w (S)-8-(2-amino-6-((R)-l-(5-chloiO-3'- 640
(methylsulfonyl)-[l ,1 '-biphenyl]-2-yl)-2,2,2- trifluoi ethoxy)pyrimidin-4-yi)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
0
x (S)-8-(2-amino-6-((R)-l-(5-chloiO-3,-cyano-[l,r- 587 biphenyl]-2-yl)-2,2i2-trifluoiOethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid y (S)-8-(2-amino-6-((R)-l -(5-chloro-3'-methoxy-[l , l '- 592 biphenyl]-2-yl)-2;2,2-tnf}uoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid z (S)-8-(2-amino-6-((R)- l-(3'-(aminomethyl)-5-chloiO- 591
[ 1 , 1 '-biphenyl]-2-yl)-2J2,2-tiifluoi ethoxy)pyrimidin- 4-yl)-2,8-diazaspiiO[4,5]decane-3-carboxylic acid
H2N
aa (S)-8-(6-((R)- 1 -(3'-(acrylamidomet yl)-5-chloiO- 645
[1,1 '-biphenyl]-2-yl)-2J2J2-trifluoiOethoxy)-2- aminopyrimidin-4-yl)-2s8-diazaspiro[4.5]decane-3- carboxylic acid
O. ,NH ab (S)-8-(2-amino-6-((R)-l-(3'-carboxy-5-chloiO-[l,l'- 606 biphenyl] -2-y l)-2 ,2,2-t rifluoroethoxy)pyrim idiii-4 - yl)-2,8-diazaspiiO[4.5]decane-3-cai'boxylic acid
OH
ac (S)-8-(2-amino-6-((R)- 1 -(3'-carbamoyI-5-chloro- 605
[1,1 '-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyi'imidin- 4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid
NH3
Figure imgf000180_0001
4202
Figure imgf000181_0001
av (S)-8-(2-amino-6-((R)-l-(3',5-dichloro-4'-fluoro- 615
[1 , -biphenyl]-2-yl)-2)252-trifluoroethoxy)pyi,imidin- 4-yl)-2,8-diazaspiio[4,5]decane-3-carboxylic acid
F
aw (S)-8-(2-amino-6-((R)-l-(5-chloiO-3',4,-difluoiO- 598
[1 ; -biphenyl]-2-yl)-2;2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4,5]decane-3-carboxylic acid
F
ax (S)-8-(2-amino-6-((R)-l-(3',5-dichlolΌ-4,- 665
(trifluoi methyl)-[l ,r-biphenyl]-2-yl)-2}2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4,5]decane-3-carboxylic acid
Figure imgf000182_0001
ay (S)-8-(2-amino-6-((R)- l-(5-chloro-3,,4'-dimethyl- 591
[l,r-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid az (S)-8-(2-amino-6-((R)-l-(5-chloiO-4'-ethoxy-3'- 625 fluoro-[l ,1 '-biphenyl]-2-yl)-2,2,2- trifluoiOethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid ba (S)-8-(2-amino-6-((R)-i-(5-chloi -3'55,-dimethyl- 591
[ 1 , V -biphenyl] -2 -y l)-2>2,2 -tr ifluor o ethoxy)pyrim idin- 4-yl)-2,8-diazaspiro 4.5]decane-3-carboxylic acidbb (S)-8-(2-amino-6-((R)-l-(5-chloiO-3'-methyl-4!- 661
(trifluoromethoxy)-[l , -biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid bc (S)-8-(2-amino-6-((R)-l-(4')5-dichlorO"3',5'- 625 dimethyl-[l ,1 '-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-238~
diazaspiio[4.5]decane-3-carboxyIic acid
Ci
bd (S)-8-(2-amino-6-((R)-l-(5-chloro-4'-fluoro-3'- 595 methyl-[l,l'-biphenyl]-2-yl)-2,2,2- tnfliioi eihoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
F
Figure imgf000183_0001
diazaspiro[4.5]decane-3-carboxylic acid 4054202
Figure imgf000184_0001
Figure imgf000185_0001
54202
Figure imgf000186_0001
34cp H (S)-8-(6-((R)-l-(2-(lH-benzo[d]imidazol-4-yl)-4- 603 chlorophenyl)-2,2,2-trifluoroethoxy)-2- aminopyrimidin-4-yl)-2, 8-diazaspitO [4.5] decane-3 - carboxylic acid
34cq (S)-8-(2-amino-6-((R)-l-(5-chloiO-3'-(piperazine-l- 675 carbonyl)-[l;r-biphenyl]-2-yl)-2,2,2- trifluoroet oxy)pyrimidin-4-yl)-258- diazaspiro[4.5]decane-3-carboxylic acid
34cr (S)-8-(2-amino-6-((R)-l-(5-chloro-3'-(4- 716 cyc J opropylpiper azine- 1 -caibony 1) -[ 1 , -biphenyl] -2- yl)-2,252-trifluoroethoxy)pyijmidin-4-y])-2,8- diazaspiro[4.5]decane-3-carboxylic acid
34cs (S)-8-(2-amino-6-((R)- 1 -(4-chloro-2-(pyridin-2- 564 yl)phenyl)-2,252-ti'ifluoiOethoxy)pyi'imidin-4-yl)-2;8- diazaspiro[4.5]decane-3-caiboxylic acid
34ct (S)-8-(2-amino-6-((R)- 1 -(4-chloro-2-(pyrimidin-2- 564 yl)phenyl)-2,2,2-tnfluoiOethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4, 5]decane-3 -carboxylic acid
34cu (S)-8-(2-amino-6-((R)-l-(4-chloro-2-(pyrazin-2- 565 yl)phenyl)-2,2>2-trifluoroethoxy)pynmidin-4-yl)-2,8- d iazaspiro [4.5 ]decane-3 -carboxyl ic acid
34cv (S)-8-(2-amino-6-((R)-I-(5-chloro-3'-(2- 637 methoxyet oxy)-[l ,r-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decaiie~3-carboxylic acid
Table 12b.
NMR Data for Compounds of Table 12a
Figure imgf000187_0001
7.22 Hz, 1 H) 2.34 (dd, J=13.37, 9.27 Hz, 1 H) 3,08 - 3.19 (m, 1H) 3.28 (d, J=11.71 Hz, 1 H) 3.38 - 3.56 (m, 2 H) 3.63 (d, J=5.66 Hz, 2 H) 4.11 (dd, J=8.98, 7.22 Hz, 1 H) 5.51 (s, 1 H) 6.66 (d, J=6.83 Hz, 1 H) 7.30 (d, J=2.15 Hz, 1 H) 7.41 - 7.52 (m, 4 H) 7.52 - 7.61 (ra, 2 H) 7.69 (d, J=8.59 Hz, 1 H)
d 'H-NMR (400 MHz, MeOH -d4): 5 ppm 1.9 (m,4H), 1.98 (m,lH), 2.26 (m,lH), 3.01 (m,lH), 3.17 (m,lH), 3.48 (m,2H), 3.60 (m,2H), 3.95 (ηι,ΙΗ), 5.53-5.52 (d,lH), 6.26- 6.22 (q,lH), 6.97-6.69 (m, 3H), 7.31-7.17(m,2H), 7.47-7.44 (m,lH), 7.74-7.63 (m,lH)e !H NMR (400 MHz, DMSO-d6): δ ppm 1.61 (m, 4 H), 2.07-2.04 (m, 1 H), 2.37-2,33 (m, 1 H), 3.15-3.12 (d, 1 H, J=l 1.8 Hz), 3.25 (d, 1 H, J=1 1.8 Hz), 3.50-3.47 (m, 2 H), 3.67- 3.66 (m, 2 H), 4.1 1-4.07 (t, 1H), 5.58 (s, 1 H), 6.58-6.53 (q, 1 H, J=6.8 Hz), 7.36 (s, 1 H), 7,53-7.51 (d, 1 H, J=8.4 Hz), 7.70-7.67 (d, 1 H, J=8.0 Hz), 7.82-7.78 (ra, 2 H), 8.38-8.36 (d, 1 H, J=8.0 Hz), 8.58 (s, 1 H)
f 'H NMR (400 MHz, MeOH -d4): δ ppm 1.58 (m, 4 H), 2.05-2.02 (m, 1 H), 2.31-2.30 (m, 1 H), 3.28-3.21 (d, 1 H, J =11.8 Hz), 3.48-3.46 (m, 2 H, J =11.8 Hz), 3.68-3.51 (m, 2 H), 4.08-4.01 (q, 1 H, J =7.0 Hz), 5.44 (s, 1 H), 6.76-6.69 (m, 4 H), 7.26-7.21 (m, 2 H), 7.41- 7.40 (d, 1 H, J =8.4 Hz), 7.66-7.64 (d, 1 H, J =8.4 Hz)
g ! H-NMR 400 MHz, MeOH -d4): δ ppm 1.28 (m,2H), 1.63 (m 4H), 2.10-2.04 (m,lH), 2.42-2.36 (m,lH), 3.19-3, 16 (d, J =6.0,2H), 3.26 (s,lH), 3.65 (m,2H), 4.28-4.24 (t, J=16.0,1H), 5.58 (s 1H), 6.62-6.57 (m, 1H), 7.37-7.36 (d, J =4.0, IH), 7.54-7.51 (dd, J=12.0, 4.0,1H), 7.72-7.70 (d, J =8.0,1H), 7.78-7.76 (d, J =8.0,2H), 8.43-8,41 (d, J=8.0,2H)
h 1 H-NMR (400 MHz, MeOH -d4): δ ppm 1.29 (m,2H), 1.58 (m,4H), 2.07-2.02 (m,lH), 2.33-2.28(m,iH), 3.1 1-3.08 (d, J=12.0,1H), 3.24-3.21 (d, J=12.0, 1H), 3.48-3.4 l(m,2H), 3,60-3.55(m,2H), 4.08-4.04 (t, J=16.0, 1H), 5.39 (d, J =2.0,1 H), 6.66-6.63 (m,lH), ), 6.86-6.84 (d, J =8.02H), 7.19-7.17 (d, J =8.0,2H), 7.25-7.24 (d, J =4,0,1H), 7.37-7.35 (dd, J -8.0, 6.0,1H), 7.63-7.61(d, J=8.0,1H)
i lK NMR (400 MHz, MeOH-d4): δ 7.88 (t, J=7.68 Hz,l H), 7.70 (d, J=8.52 Hz,l H), 7.50 (m, 3 H), 7.35 (d, J=7.76 Hz,l H), 6.99 (q, J=6.96 Hz, IH), 5.69 (s, 1 H), 4.06 (t, J=7.48 Hz,2 H), 3.62 (m, 2 H), 3.48 (m, 2 H), 3.22 (d,J=l 1.64 Hz, 1H),3.09 (d, J=l 1.44 Hz,l H), 2.61 (s, 3 H), 2.30 (m, 1 H), 2.03 (m,lH), 1.57 (m, 4 H).
j lH NMR (400 MHz, MeOH-d4): δ ppm 1.25 (t, J = 7.4 Hz, 3H), 1.63 (m, 4H), 2.11-2.06 (m, IH), 2.38-2.31 (m, IH), 3.16-3.13 (m, IH), 3.26 (m, IH), 3.31 (m, 2H), 3.55-3.50 (m, 2H), 3.71-3.64 (m, 2H), 4.11 (M, IH), 5.61 (s, IH), 6.63 (m, IH) , 7.36 (s, IH), 7.52- 7.50 (m, IH), 7.71-7.68 (m, IH), 7.76-7.75 (m, IH), 7.83 (t, J = 7.8 Hz, IH), 8.04 (d, J = 7.2 Hz, IH) 8.43 (s, IH)
k Ή NMR (400 MHz, MeOH -d4): δ ppm 0.96 (t, J=12.0} 4H), 1.70-1.62 (ra, 8H), 2.06 (s, IH), 2,32 (s, 1H),3.24 (d, J - 12.0, IH), 3.50(s, 2H), 3.67(8, 2H), 4.07 (s, IH), 4.63 (s, IH), 5.61 (s, IH), 6.62 (q, J=8.0, IH), 7.37(s,lH), 7.50 (d,lH,J=8.0),7.79-7.69 (m,2H), 7.83(t,lH,J=8.0), 8.03(d,lH,J=8.0), 8.45 (s, IH)
1 'H NMR (400 MHz, MeOH-d4): δ ppm 8.47 (s, 1 H), 8.03 (d, 1 H), 7.74 (t, 1 H), 7.67 (m, 2 H), 7.51-7.49 (d, 1 H), 7.37 (s, 1 H), 6.64-6.59 (q, 1 H), 5.62 (s, 1 H), 4.12-4.08 (t, 1 H), 3.67 (m, 2 H), 3.50 (m, 2 H), 3.26 (d, 1 H), 3.13 (d, 1 H), 2.35-2.32 (m, 1 H), 2.05 (m, 1 H), 1.63 (m, 6 H), 1.34 (q, 2 H), 0.84-0.80 (t, 3 H)
m Ή NMR (400 MHz, MeOH -d4): δ ppm 7.74-7.66 (m, 2H), 7.48-7.39 (m, 3H), 7,27 (m, 2H), 6.73-6.71 (m, IH), 5.53 (s, IH), 4.73 (s, 2H), 4.08 (t, J = 7.1 Hz, IH), 3.63 (m, 2H), 3.47 (m, 2H), 3.27-3.24 (m, IH), 3.14-3.11 (m, IH), 2.36-2.30 (m, IH), 2.08-2,03 (m, IH), 1.60 (m, 4H)
η Ή NMR (400 MHz, MeOH -d4)6 ppm 7.66 (d, 1 H,J=8.6 Hz), 7.50 (m, 3 Η), 7.31 (m, 2 H), 7.24 (d, 1 H,J=8.2 Hz), 6.61 (m, 1 H), 4.21 (ra, 1 H), 3.63 (m, 2 H), 3.48 (m, 2 Η), 3.21 (m, 1 H), 3.18 (m, 1 H), 3.01 (s, 3 H), 2.37 (m, 1 H),2.07 (m, 1 H), 1.62 (m, 4 H)ο Ή-NMR (400 MHz, MeOH-d4); δ ppm 7.97 (s.lH) ,7.60-7.67 (m,2H) ,7.52-7.54
(m,lH),7.40 -7.46 (m, 1H),7.31 - 7.31 (m, IH), 7.22 - 7.24 (m,lH),6.61 -6.66 (m, IH), 5.51 (s, IH), 4.39 -4.04 (m, 4H), 3.52 -3.60 (m,2H), 3.42 -3.50 (m, 2H), 3.15 -3.18 (d,lH), 2.96 -2.99 (d,l H), 2.60 -2.64 (m, 2H), 2.18 -2.28 (ra, 3H),1.96 -2.00 (m, IH), 1.58 -1.59 (m, 4H)
ρ 'H-NMR (400 MHz, DMSO-d6): δ ppm 8.00 (s,lH), 7.56 -7.58 (m,lH), 7.43 -7.49
(m,2H), 7.26 -7.27 (ra, 2H), 6.97 -7.97 (m, IH), 6.59 -6.55 (mslH), 5.48 (s, IH), 3.78 - 3.82 (m, IH), 3.70 -3.74 (m,2H), 3.39-3.44 (m, 6H), 2.98 -3.02 (d,lH), 2.82 -2.85 (d,lH), 2.70 (s, 3H), 2.04 -2.1 1 (m, IH), 1.69 -1.75 (m, IH), 1.36 -1.40 (m, 4H)
q Ή NMR (400 MHz, MeOH-d4): δ ppm 1.64 (t, J = 5.8 Hz, 4H), 2,08 (dd, J = 13.5, 7,6 Hz, IH), 2.40 (dd, J = 13.5, 9,0 Hz, IH), 3.19 (d, J = 11.8 Hz, IH), 3.28 (d, J = 12.2 Hz, I H), 3.51 (m, 2H), 3.66 (m, 2H), 4.28 (t, J = 8.4 Hz, IH), 4.87 (s, 16H), 6.53 (q, J = 6,7 Hz, IH), 7.34 (d, J = 2.3 Hz, IH), 7.51 (dd, J = 8.6, 2.3 Hz, IH), 7.75 (m, 5H)r Ή NMR (400 MHz, MeOH-d) 8 ppm 1.62 (d, J-4.88 Hz, 4 H) 2.08 (dd, J=13,47, 7,22 Hz, 1 H) 2.34 (dd, J=13.37, 9.27 Hz, 1 H) 3.08 - 3.19 (ra, IH) 3.28 (d, J=11.71 Hz, 1 H) 3.38 - 3.56 (m, 2 H) 3.63 (d, J=5.66 Hz, 2 H) 4.11 (dd, J=8.98, 7.22 Hz, 1 H) 5.51 (s, 1 H) 6.66 (d, J=6.83 Hz, 1 H) 7.30 (d, J=2.15 Hz, 1 H) 7.41 - 7.52 (m, 4 H) 7.52 - 7.61 (m, 2 H) 7.69 (d, J=8.59 Hz, 1 H)
s ]H NMR (400 MHz, MeOH-d4): δ ppm 1.60 (d, JM5.47 Hz, 4 H) 1.98 - 2.12 (m, 1 H) 2,26 - 2.39 (ra, 1 H) 3.07 - 3.17 (m, 1 H) 3,20 - 3.29 (m, 1 H) 3.38 - 3.55 (m, 2 H) 3.56 - 3.71 (m, 2 H) 4.01 - 4,15 (m, 1 H) 5.51 (s, 1 H) 6.74 - 6.89 (m, 1 H) 7.11 (s, 1 H) 7.14 (s, 1 H) 7.42 (d, J=2.15 Hz, 11 H) 7.44 - 7.53 (ra, 1 H) 7.61 - 7.73 (m, 1 H)
t ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.51 (d, J=4.69 Hz, 4 H) 1.84 - 2.00 (m, 1 H) 2.09 - 2.31 (m, 1 H) 2.82 - 3.00 (m, 1 H) 3.02 - 3.20 (m, 1 H) 3.32 - 3.64 (m, 4 H) 3,84 - 3.94 (m, 1 H) 3,98 (s, 3 H), 5.50 (s, 1 H) 6.63 (d, J=1.95 Hz, 1 H) 7.13 - 7.27 (m, 1 H) 7.39 (d, J=1.56 Hz, 1 H) 7.55 (d, J=1.76 Hz, 1 H) 7.64 (d, J=8.59 Hz, 1 H) 7.71 (d, J=1.76 Hz, 1 H)
u Ή NMR (400 MHz, MeOH-d4): δ ppm 1.52 - 1 ,75 (m, 4 H) 2.07 (dd, J-13.40, 7.30 Hz, 1 H) 2.34 (dd, J 3.42, 9.18 Hz, 1 H) 3.07 - 3.29 (m, 2 H) 3.40 - 3,78 (m, 4 H) 4.10 (dd, J=9.10, 7.25 Hz, 1 H) 5.59 (s, 1 H) 6.61 (q, J=6.59 Hz, 1 H) 7.31 (d, J=2.20 Hz, 1 H) 7.49 (dd, J=8.52, 2.22 Hz, 1 H) 7.61 (d, J=7.03 Hz, 1 H) 7.65 - 7.80 (m, 2 H) 7.97 - 8.10 (m, 1 H) 8.32 (br. s., 1 H)
v Ή NMR (400 MHz, MeOH-d4): δ ppm 1.52 - 1.71 (m, 4 H) 2.07 (dd, J=13.42, 7,27 Hz, 1 H) 2.33 (dd, J=13.47, 9.27 Hz, 1 H) 3.08 - 3.29 (m, 2 H) 3.36 - 3.76 (m, 4 H) 4.09 (dd, J=9.15, 7.20 Hz, 1 H) 5.48 (s, 1 H) 6,74 (q, J=7.00 Hz, 1 H) 6.87 (d, J=7.47 Hz, 1 H) 6.91 (ddd, J=8.19, 2.48, 0.85 Hz, 1 H) 7.05 (d, J=0.73 Hz, 1 H) 7.28 (d, J=2.20 Hz, 1 H) 7.32 (t, J=7.88 Hz, 1 H) 7.43 (dd, J=8.49, 2.25 Hz, 1 H) 7,67 (d, J=8.49 Hz, 1 H)w fH NMR (400 MHz, MeOH-d4): δ ppm 1.43 - 1.76 (m, 4 H) 2.08 (dd, J=13.45, 7.15 Hz, 1 H) 2.34 (dd, J=13.42, 9.22 Hz, 1 H) 3.13 - 3.29 (m, 5 H) 3.41 - 3.77 (m, 4 H) 4.10 (dd, J=9.18, 7.17 Hz, 1 H) 5.60 (s, 1 H) 6.57 (q, J=6.57 Hz, 1 H) 7.35 (d, J=2.15 Hz, 1 H) 7,51 (dd, J=8.52, 2.17 Hz, 1 H) 7.70 (d, J=8.54 Hz, 1 H) 7.72 - 7.78 (m, 1 H) 7.78 - 7.87 (m, 1 H) 8.04 - 8. 5 (m, 1 H) 8,41 (d, J=0.39 Hz,l H) x !H NMR (400 MHz, DMSO-d6): δ ppm 1.46 - 1.69 (m, 4 H) 1.90 (dd, J=13.25, 9.20 Hz, 1 H) 2.35 (dd, J-13.35, 8.66 Hz, 1 H) 3.14 (br. s., 2 H) 3.64 (br. s., 4 H) 4.45 (t, J=6.49 Hz, 1 H) 5.84 (br. s., 1 H), 6.56 (q, J=6.77 Hz, 1 H) 7.48 (d, J=1.07 Hz, 1 H) 7.62 - 7.69 (m, 2 H) 7.75 - 7.82 (m, 1 H) 7.83 - 7.91 (m, 1 H) 7.92 - 8.00 (m, 2 H) 8.97 (br. s„ 1 H) 10.23 (br. s., 1 H)
y 'H NMR (400 MHz, DMSO-d6): δ ppm 1.46 - 1.71 (m, 4 H) 1.91 (dd, J=13.32, 9.27 Hz, 1 H) 2.27 - 2.40 (m, 1 H) 3.14 (br. s., 2 H) 3.63 (d, J=5.37 Hz, 4 H) 3.81 (ss 3 H) 4.36 - 4.53 (m, 1 H) 5.85 (br. s.,1 H) 6.72 (q, J-6.62 Hz, 1 H) 6.94 - 7.10 (m, 3 H) 7.40 (d, J=2.05 Hz, 1 H) 7.49 (t, J=7.96 Hz, 1 H) 7.57 - 7.70 (m, 2 H) 8.96 (d, J=5.71 Hz, 1 H) 10.27 (br. s., 1 H)
z Ή NMR (400 MHz, DMSO-d6): δ ppm 1.43 - 1.76 (m, 4 H) 1.92 (dd, JM13.18, 9.32 Hz, 1 H) 2.35 (dd, 1=13.30, 8,57 Hz, 1 H) 3.14 (br. s., 2 H) 3.67 (br. s., 4 H) 3.97 - 4.18 (m, 2 H) 4.44 (t, J=6.88 Hz, 1H) 5.93 (br, s., 1 H) 6.75 (q, J=6.57 Hz, 1 H) 7.39 (d, J=l .66 Hz, 1 H) 7.53 (br. s.5 1 H) 7.57 - 7.71 (m, 5 H) 8.58 (br. s, 3 H) 9.01 (br. s., 1 H) 10.55 (br. s., 1 H)
aa Ή NMR (400 MHz, MeOH-d4): δ ppm 1.68 - 1.86 (m, 5 H) 2.13 (dd, J=13,69, 8.66 Hz, 1 H) 2.54 (dd, J=13.72, 8,98 Hz, 1 H) 3.56 (br. s., 1 H) 3.67 (br. s., 3 H) 4.44 - 4.63 (m, 3 H) 5.70 (dd, J=9.42,2.54 Hz, 1 H) 6.19 - 6.35 (ra, 2 H) 6.58 (br. s., 1 H) 7.28 (d, J=7.57 Hz, 1 H) 7.34 - 7.40 (m, 2 H) 7.43 (d, J=7.86 Hz, 1 H) 7.47 - 7.56 (m, 2 H) 7.71 (d, J=8.64 Hz, 1 H)
ab >H NMR (400 MHz, DMS0-d6): δ ppm 1.44 - 1.69 (m, 4 H) 1.91 (dd, J=13.28, 9.18 Hz, 1 H) 2.35 (dd, J=13.15, 8,61 Hz, 1 H) 3.14 (br. s., 2 H) 3.64 (br. s., 4 H) 4.37 - 4.53 (m, 1 H) 5.87 (br. s., 1 H) 6.62 (q, J=6.78 Hz, 1 H) 7.43 (t, J=1.22 Hz, 1 H) 7.65 (s, 2 H) 7.70 (d, J=4.78 Hz, 2 H) 7.99 - 8.12 (m, 1 H) 8.26 (br. s., 1 H) 8.96 (d, J=5.03 Hz, 1 H) 10.25 (br. s., 1 H)
ac >H NMR (400 MHz, MeOH-d4): δ ppm 1.62 (d, J=4, 15 Hz, 4 H) 2.02 - 2.14 (m, 1 H) 2.26 - 2.43 (m, 1 H) 3,08 - 3.29 (m, 2 H) 3.40 - 3.77 (m, 4 H) 4.09 (dd, J=8.98, 7.27 Hz, 1 H) 5.55 (s, 1 H) 6,55 - 6.70 (m5 1 H) 7.30 (d, J=2.05 Hz, 1 H) 7.47 (dd, J=8.47, 2.07 Hz, 1 H) 7.51 - 7.59 (m, 1 H) 7.59 - 7.65 (m, 1 H) 7.67 (d, J=8.30 Hz, 1 H) 7.96 (dd, J=8.52, 1.00 Hz, 1 H) 8.32 - 8.50 (m, 1 H)
ad •H NMR (400 MHz, MeOH-d4): δ ppm 1.50 - 1.76 (m, 4 H) 2.07 (dd, J=13.20, 7.15 Hz, 1 H) 2.34 (dd, J=13.47, 9.27 Hz, 1 H) 3.14 (d, J-l 1.71 Hz, 1 H) 3.23 (s, 3 H) 3.27 (d, J=l 1.86 Hz, 1 H) 3.40 - 3.76 (m, 4 H) 4.09 (dd, J=9.03, 7.27 Hz, 1 H) 5.54 (s, 1 H) 6.60 (q, J=6.64 Hz, 1 H) 7.34 (d, J=2.15 Hz, 1 H) 7.52 (dd, J=8.49, 2.20 Hz, 1 H) 7.72 (d, J=8.54 Hz, 1 H) 7.78 (d, J-7.76 Hz, 2 H) 8.14 (d, J=8.64 Hz, 2 H)
ae Ή NMR (400 MHz, MeOH-d4): δ ppm 1.61 (q, J=4.88 Hz, 4 H) 2.07 (dd, J=13.37, 7.13 Hz, 1 H) 2.33 (dd, J-13.42, 9.22 Hz, 1 H) 3.08 - 3.30 (m, 2 H) 3.38 - 3.74 (m, 4 H) 4.10 (dd, J=8.91, 7.35 Hz, 1 H), 5.52 (s, 1 H) 6.53 - 6.69 (m, 1 H) 7.33 (d, J=2.20 Hz, 1 H) 7.50 (dd, J=8.52, 2.22 Hz, 1 H) 7.67 (d, J=7.96 Hz, 2 H) 7.71 (d, J=8.54 Hz, 1 H) 8.08 (d, J=8.64 Hz, 2 H)
af Ή NMR (400 MHz, MeOH-d4): δ ppm 1.62 (q, J = 6.0, 5.0 Hz, 17H), 2.07 (dd, J = 13.4, 7.2 Hz, 5H), 2.33 (dd, J = 13.4, 9.2 Hz, 5H), 3.15 (d, J = 11.8 Hz, 5H), 3.27 (d, J = 11.8 Hz, 13H), 3.49 (m, 9H), 3.64 (ddt, J = 15.7, 0.7, 5,2 Hz, 9H), 4, 1 1 (dd, J = 9.2, 7.1 Hz, 5H), 6.61 (q, J = 6.7 Hz, 4H), 7.33 (m, 7H), 7.47 (m, 8H), 7.66 (m, 8H)
ag Ή NMR (400 MHz, MeOH-d4): δ ppm 0,86 (m, 1H), 1.34 (dd, J = 9.4, 6.0 Hz, 7H), 1.58 (t, J = 5.7 Hz, 4H), 1.98 (dd, J = 13.3, 7.0 Hz, 1H)} 2.26 (dd, J = 13.3, 9.0 Hz, 1H), 3.00 (d, J = 1 1.5 Hz, IH), 3,16 (d, J = 11.5 Hz, IH), 3.46 (ddt, J = 19.2, 12.6, 5.9 Hz, 2Η), 3.62 (dt, J = 12.8, 7.1 Hz, 2H), 3.96 (t, J = 8.1 Hz, IH), 4.69 (p, J = 6.0 Hz, IH), 5,50 (s, IH), 6.73 (q, J = 6.9 Hz, IH), 6.95 (m, IH), 7.04 (dd, J = 8.5, 2.4 Hz, IH), 7.20 (s, IH), 7.28 (d, J = 2.3 Hz, IH), 7.42 (m, 2H), 7.66 (d, J = 8.5 Hz, IH)
ah Ή NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 7.3 Hz, IH), 1 ,41 (t, J = 7.0 Hz, 3H), 1.61 (q, J = 6.2, 5.4 Hz, 4H), 2.07 (dd, J - 13.5, 7.3 Hz, IH), 2.35 (dd, J = 13.5, 9.1 Hz, IH), 3.14 (d, J = 1 1.8 Hz, IH), 3.26 (d, J = 1 1.7 Hz, IH), 3,33 (s, IH), 3.48 (m, 2H), 3.66 (dd, J = 14.5, 6.2 Hz, 2H), 4.13 (tt, J = 9.7, 7.2 Hz, 3H), 4.87 (s, 17H), 6.74 (q, J = 6.9 Hz, 1H), 6.97 (d, J = 7.6 Hz, IH), 7,04 (dd, J = 8.3, 2.5 Hz, lH), 7.19 (s, IH), 7.29 (d, J = 2.2 Hz, IH), 7.44 (m, 2H), 7.67 (d, J = 8.5 Hz, IH)
ai Ή NMR (400 MHz, MeOH-d4): δ ppm 1 ,48 (t, J = 7,0 Hz, 3H), 1.60 (m, 4H), 2.06 (dd, J = 13.4, 6.9 Hz, IH), 2.33 (dd, J = 13.4, 8.9 Hz, IH), 3.13 (d, J = 11.6 Hz, lH), 3.25 (d, J = 11.4 Hz, IH), 3.48 (ddd, J = 21 ,0, 14.2, 7,2 Hz, 2H), 3.64 (q, J = 8.9, 8.1 Hz, 2H), 4,09 (t, J = 8.3 Hz, IH), 4.20 (q, J = 6.9 Hz, 2H), 4.88 (s, 15H), 5.52 (s, IH), 6.63 (q, J = 6.7 Hz, IH), 7.24 (m, 2H), 7.34 (d, J - 8.3 Hz, IH), 7.43 (dd, J = 8.5, 2.3 Hz, 2H), 7.57 (s, IH), 7.65 (d, J = 8.4 Hz, IH)
aj !H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, IH), 1.58 (dd, J = 7.1 , 4.1 Hz, 4H), 1.99 (dd, J = 13.4, 7.1 Hz, IH), 2.29 (m, IH), 2.46 (s, 3H), 3.02 (d, J = 11.6 Hz, IH), 3.18 (d, J = 1 1.6 Hz, IH), 3,46 (ddt, J = 21.0, 13.5, 6.0 Hz, 2H), 3.63 (m, 2H), 3.98 (dd, J = 9,2, 7.1 Hz, IH), 5.52 (s, IH), 6.60 (q, J = 6.6 Hz, IH), 7.28 (m, 2H), 7.45 (dd, J = 8.3, 2,4 Hz, 2H), 7.56 (m, IH), 7.66 (d, J = 8.5 Hz, IH)
ak lH NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 6.2 Hz, IH), 1.40 (d, J = 6.0 Hz, 6H), 1.60 (d, J = 5.2 Hz, 4H), 2.03 (dd, J = 13.4, 6.8 Hz, IH), 2.30 (dd, J = 13,3, 8.9 Hz, IH), 2,81 (s, IH), 3.07 (d, J = 11.6 Hz, IH), 3.22 (d, J = 11.8 Hz, IH), 3.48 (m, 2H), 3.64 (d, J = 9.7 Hz, 2H), 4.03 (t, J = 7.9 Hz, IH), 4.75 (m, IH), 5,53 (s, IH), 6.63 (q, J = 6.8 Hz, IH), 7.29 (m, 3H), 7.43 (dd, J = 8.6, 2.3 Hz, IH), 7.58 (s, IH), 7.65 (d, J - 8.5 Hz, IH)
al ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.39 (d, J = 6,0 Hz, 6H), 1.60 (m, 4H), 2.06 (dd, J = 13,5, 7.2 Hz, IH), 2.33 (dd, J = 13.4, 9.2 Hz, IH), 3.13 (d, J = 1 1.7 Hz, IH), 3.26 (d, J = 1 1.7 Hz, IH), 3.48 (m, 2H), 3,64 (q, J = 12.4, 10.4 Hz, 2H), 4.10 (dd, J = 9,2, 7.2 Hz, IH), 4.70 (hept, J = 5,9 Hz, IH), 5.53 (s, IH), 6.67 (q, J = 6.8 Hz, IH), 7.25 (m, 4H), 7.43 (dd, J = 8,5, 2.3 Hz, IH), 7.65 (d, J = 8.4 Hz, IH)
am ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, IH), 1.61 (q, J = 5.7 Hz, 4H), 2.06 (dd, J = 13.4, 7.1 Hz, 1H), 2.33 (dd, J = 13.4, 9.2 Hz, IH), 3.12 (d, J = 1 1.7 Hz, IH), 3.26 (d, J = 11.6 Hz, IH), 3.48 (ddt, J = 18.1, 13.6, 6.0 Hz, 2H), 3.65 (tt, J = 1 1.7, 4.8 Hz, 2H), 4.08 (dd, J = 9.2, 7.1 Hz, IH), 5.54 (s, IH), 6.49 (q, J = 6.6 Hz, IH), 7.35 (d, J = 2.2 Hz, IH), 7.51 (dd, J = 8.5, 2.3 Hz, IH), 7.69 (d, J = 8.5 Hz, IH), 7.82 (td, J = 17.6, 16.6, .9 Hz, 3H)
an Ή NMR (400 MHz, MeOH~d4): δ ppm 0.88 (d, J = 7.8 Hz, IH), 1.29 (d, J = 6.7 Hz, 2H), 1.62 (q, J = 5.9, 5.4 Hz, 4H), 2.07 (dd, J = 13.4, 7.2 Hz, H), 2.33 (dd, J = 13.4, 9.2 Hz, IH), 3.13 (d, J = 11.7 Hz, IH), 3.26 (d, J = 11.7 Hz, IH), 3.49 (ddd, J = 21.4, 12.5, 5.9 Hz, 2H), 3,65 (td, J = 12.3, 10.3, 5.5 Hz, 2H), 4.10 (dd, J = 9.2, 7.1 Hz, IH), 5.55 (s, IH), 6.59 (q, J = 6.7 Hz, I H), 7.25 (d, J = 14.9 Hz, IH), 7.35 (m, 2H), 7.44 (s, IH), 7.51 (dd, J = 8.5, 2.2 Hz, IH), 7,69 (d, J = 8.5 Hz, IH)
ao lH NMR (400 MHz, MeOH-d4): δ ppm 0.89 (m, 2H), 1 ,30 (d, J = 1 1 ,8 Hz, 3H), 1.36 (s, 10H), 1 ,60 (m, 5H), 2.34 (s, IH), 2.81 (s, IH), 3.14 (d, J = 1 1.6 Hz, IH), 3.28 (m, 4H), 3.45 (s, 2H), 3.62 (s, 3H), 4.15 (t, J = 8.1 Hz, IH), 4.85 (s, 38H), 6.62 (t, J = 6.7 Hz, IH), 7.28 (m, 2H), 7.46 (m, 5H), 7,66 (d, J = 8.5 Hz, IH)
ap 'H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 7.5 Hz, 2H), 1.65 (s, 3H), 2.08 (dd, J = 13.5, 7.9 Hz, IH), 2.44 (t, J = 1 1.2 Hz, IH), 3.24 (dd, J = 14.0, 1 1.6 Hz, IH), 3.61 (m, 4H), 4.41 (t, J - 8.4 Hz, IH), 6,48 (q, J = 6.6 Hz, IH), 7.38 (d, J = 2.2 Hz, IH), 7.54 (dd, J = 8.5, 2.2 Hz, 1H), 7.71 (d, J = 8.6 Hz, IH), 7.86 (t, J = 1.5 Hz, 2H)
aq *H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (d, J = 2,2 Hz, IH), 1 ,60 (s, 4H)5 2.03 (d, J = 13.1 Hz, IH), 2.30 (t, J = 1 1.1 Hz, H), 3.08 (d, J = 1 1.6 Hz, IH), 3.23 (d, J = 12.3 Hz, IH), 3.50 (dt, J = 24.2, 8.0 Hz, 2H), 3.64 (d, J = 10.2 Hz, 2H), 4.03 (t, J = 7,8 Hz, IH), 4.58 (s, IH), 5.55 (s, IH), 6.52 (q, J = 6.7 Hz, IH), 7.37 (d, J = 2.2 Hz, IH), 7.53 (dd, J = 8.5, 2.3 Hz, IH), 7.66 (m, 4H)
ar !H NMR (400 MHz, MeOH-d4): δ ppm 1.57 (q, J = 7.9, 6.6 Hz, 4H), 1 ,92 (dd, J = 13.2, 7.0 Hz, IH), 2.19 (dd, J = 13.2, 9.0 Hz, IH), 2.88 (d, J = 11.4 Hz, IH), 3.10 (d, J = 1 1.4 Hz, H), 3.45 (ddt, J = 20.3, 13.1, 6.1 Hz, 2H), 3.61 (m, 2H), 3.87 (s, 4H), 5,48 (s, IH), 6.70 (q, J = 6.9 Hz, IH), 7.04 (m, 2H), 7.16 (s, IH), 7.29 (d, J = 2,2 Hz, IH), 7.45 (m, 2H), 7.67 (d, J = 8.5 Hz, IH)
as !H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 10.0 Hz, 2H), 1.61 (d, J = 5.6 Hz, 5H), 2.06 (dd, J = 13.4, 7,2 Hz, IH), 2.33 (dd, J = 13.4, 9.2 Hz, IH), 3.13 (d, J = 1 1.7 Hz, IH), 3.26 (d, J = 1 1.7 Hz, IH), 3.49 (dt, J = 21.9, 7.2 Hz, 3H), 3.65 (ddt, J = 15.1, 10.1, 5.2 Hz, 3H), 4.09 (dd, J = 9.2, 7.1 Hz, IH), 4.86 (s, 26H), 5.53 (s, IH), 6.64 (q, J = 6,8 Hz, IH), 7.28 (m, 5H), 7.47 (dd, J = 8.5, 2.3 Hz, IH), 7.55 (m, IH), 7.68 (d, J = 8.5 Hz, IH)
at ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, IH), 1.35 (s, IH), 1.60 (q, J = 5.1 Hz, 4H), 2.03 (dd, J = 13.3, 7.1 Hz, IH), 2.30 (dd, J = 13.4, 9.1 Hz, IH), 2.45 (s, 3H), 3.08 (d, J = 1 1 ,6 Hz, IH), 3.23 (d, J = 11.7 Hz, IH), 3.31 (s, 3H), 3.47 (ddt, J = 19.8, 12.7, 5.7 Hz, 2H), 3.63 (dt, J = 12.9, 7,5 Hz, 2H), 4.04 (dd, J - 9.0, 7.3 Hz, IH), 5.51 (s, IH), 6.62 (q, J = 6.8 Hz, IH), 7.30 (m, 3H), 7.45 (dd, J = 8.5, 2.3 Hz, IH), 7.52 (d, J = 8.1 Hz, IH), 7.66 (d, J = 8.5 Hz, IH)
au Ή NMR (400 MHz, MeOH-d4): δ ppm .29 (d, J = 6.2 Hz, IH), 1.62 (q, J = 5.5 Hz, 4H), 2.07 (dd, J = 13.5, 7.3 Hz, IH), 2.35 (dd, J = 13.5, 9.2 Hz, IH), 3.15 (d, J = 1 1.8 Hz, lH), 3,27 (d, J = 1 1.7 Hz, IH), 3.49 (ddt, J = 21. , 13.6, 6.3 Hz, 2H), 3.66 (ddt, J = 15.6, 10.1 , 4.9 Hz, 2H), 4.14 (dd, J = 9.1, 7.3 Hz, IH), 4.85 (d, J - 3.1 Hz, 16H), 6.63 (q, J = 6.8 Hz, IH), 7.12 (m, 3H), 7.34 (d, J = 2.2 Hz, IH), 7.50 (dd, J = 8.5, 2.2 Hz, IH), 7.69 (d, J = 8.5 Hz, IH)
av Ή NMR (400 MHz, MeOH-d4): δ ppm 0.88 (m, IH), 1.28 (s, 3H), 1 ,61 (q, J = 6.1 Hz, 4H), 2.07 (dd, J = 13.4, 7.1 Hz, IH), 2.33 (dd, J = 13.5, 9.0 Hz, IH), 3.13 (d, J = 11.6 Hz, IH), 3.26 (d, J = 11.8 Hz, 2H), 3.48 (ddt, J = 20.7, 12.7, 5.7 Hz, 2H), 3.65 (q, J = 8.9, 6.2 Hz, 2H), 4.10 (m, IH), 4.90 (s, IH), 5.55 (s, IH), 6.57 (q, J = 6.8 Hz, IH), 7.42 (m, 5H), 7,67 (d, J = 8.3 Hz, 2H)
aw ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.29 (t, J - 7.7 Hz, 2H), 1.60 (q, J = 6.1, 4.9 Hz, 4H), 2.03 (dd, J = 13.3, 7.1 Hz, IH), 2.30 (dd, J = 13.4, 9.0 Hz, IH), 3.07 (d, J = 1 1.6 Hz, IH), 3.22 (d, J = 11,6 Hz, IH), 3.48 (ddt, J = 20.9, 13.3, 5.7 Hz, 2H), 3.64 (tt, J = 10.8, 5.3 Hz, 2H), 4.03 (t, J = 8.1 Hz, IH), 4.87 (s, 17H), 5.54 (s, IH), 6.61 (q, J = 6.7 Hz, IH), 7.32 (t, J = 5.0 Hz, 2H), 7.46 (m, 3H), 7.54 (s, IH), 7.67 (d, J = 8.5 Hz, IH)
ax !H MR (400 MHz, MeOH-d4): δ ppm 1.30 (dd, J = 17.9, 6.7 Hz, 2H), 1.54 (m, 4H), 1 ,79 (dd, J = 12.9, 7.0 Hz, IH), 2.06 (td, J = 16.5, 14.8, 7.8 Hz, IH), 2.66 (d, J = 11.0 Hz, 1H), 2.97 (d, J = 1 1.1 Hz, IH), 3.45 (ddt, J = 20.1, 13.2, 6.0 Hz, 2H), 3.62 (m, 3H), 5.50 (d, J = 16.5 Hz, IH), 6.54 (q, J = 6.7 Hz, IH), 7.34 (d, J = 2.3 Hz, IH), 7.52 (dd, J = 8.5, 2.3 Hz, IH), 7.68 (dd, J = 24.2, 8.1 Hz, 2H), 7.84 (m, IH), 7.97 (d, J = 8.1 Hz, IH)ay lH NMR (400 MHz, MeOH-d4): δ ppm 0.89 (m, 2H), 1.28 (s, 2H), 1.40 (s, 10H), 1.60 (q, J = 5.5 Hz, 4H), 2.06 (dd, J = 13.5, 7.1 Hz, IH), 2.35 (d, J = 3.7 Hz, 7H), 3.13 (d, J = 11.6 Hz, IH), 3.25 (d, J = 11.6 Hz, 111), 3.47 (dq, J = 22.4, 7.8, 6.8 Hz, 2H), 3.63 (dd, J = 13.9, 7.3 Hz, 2H), 4.11 (t, J = 8.3 Hz, IH), 6.66 (q, J = 6.8 Hz, IH), 7.17 (d, J - 7.1 Hz, 2H), 7.26 (m, 2H), 7.41 (dd, J = 8.5, 2.2 Hz, IH), 7.65 (d, J = 8.5 Hz, IH)
az Ή NMR (400 MHz, MeOH-d4): δ ppm 0.88 (q, J - 10,5, 8.0 Hz, IH), 1.30 (d, J = 12.4 Hz, 4H), 1.46 (t, J = 7.0 Hz, 5H), 1.61 (d, J = 5.7 Hz, 8H), 2.06 (dd, J = 13.4, 7.1 Hz, 2H), 2.33 (dd, J = 13.3, 8.8 Hz, 2H), 3.13 (d, J = 11.5 Hz, 2H), 3.26 (d, J = 11.8 Hz, 2H), 3.48 (m, 4H), 3.62 (d, J = 12.9 Hz, 3H), 4.19 (m, 5H), 4.84 (s, 2H), 6.67 (q, J = 6.7 Hz, 2H), 7.27 (m, 7H), 7.43 (dd, J = 8.6, 2.2 Hz, 2H), 7.65 (d, J = 8.5 Hz, 2H)
ba IH NMR (400 MHz, MeOH-d4): δ ppm 1.59 (m, 4H), 2.04 (dd, J = 13.4, 7.2 Hz, IH), 2.38 (s, 7H), 3.08 (d, J = 1 1.7 Hz, IH), 3.23 (d, J = 1 1.7 Hz, IH), 3.46 (m, 2H), 3.64 (dt, J = 14.7, 5.8 Hz, 2H), 4.04 (dd, J = 9.2, 7.1 Hz, IH), 5.48 (s, IH), 6.67 (q, J = 6,9 Hz, IH), 7.03 (s, 2H), 7.12 (s, IH), 7.25 (d, J = 2.3 Hz, IH), 7.42 (dd, J = 8.5, 2.3 Hz, IH), 7.66 (d, J = 8.5 Hz, IH)
bb ]H NMR (400 MHz, MeOH-d4): δ ppml .28 (s, 3H), 1.58 (m, 4H), 1.98 (dd, J = 13.2, 7.1 Hz, IH), 2,25 (dd, J = 13.3, 9.1 Hz, IH), 2.40 (s, 3H), 2.98 (d, J = 1 1.5 Hz, IH), 3.17 (d, J = 1 1.5 Hz, IH), 3.46 (ddt, J = 20.0, 13,0, 6.1 Hz, 2H), 3.63 (dq, J = 12.7, 6,3 Hz, 2H), 3.95 (dd, J = 9.1, 7.0 Hz, IH), 4.89 (s, 17H), 5.52 (s, IH), 6.61 (q, J = 6,7 Hz, IH), 7.30 (d, J = 2.3 Hz, IH), 7.46 (m, 4H), 7.67 (d, J = 8.4 Hz, IH)
bc Ή NMR (400 MHz, MeOH-d4): δ ppm0.88 (d, J = 7.5 Hz, IH), 1.28 (s, 3H), 1.60 (q, J = 5.5 Hz, 4H), 2.05 (dd, J = 13.6, 7.3 Hz, IH), 2.30 (m, IH), 2.44 (d, J = 2.6 Hz, 6H), 3.10 (d, J = 1 1.7 Hz, IH), 3,26 (m, 2H), 3.47 (ddd, J = 16.0, 12.4, 6.6 Hz, 2H), 3.62 (d, J = 12.7 Hz, 2H), 4.06 (dd, J = 9.2, 7.2 Hz, IH), 5.50 (d, J = 2.5 Hz, IH), 6.64 (q, J = 6.7 Hz, IH), 7.21 (s, 2H), 7.27 (d, J = 2.3 Hz, IH), 7.44 (dd, J = 8.5, 2.3 Hz, IH), 7,66 (d, J = 8.5 Hz, IH)
bd Ή NMR (400 MHz, MeOH-d4): δ ppm 0.89 (t, J = 7.7 Hz, IH), 1.29 (d, J = 5.9 Hz, 5H), 1.61 (q, J = 5.6 Hz, 4H), 2.06 (dd, J = 13.5, 7,2 Hz, IH), 2.33 (m, 4H), 2.84 (s, IH), 3.12 (d, J = 11.7 Hz, IH), 3.25 (d, J = 11.7 Hz, IH), 3.48 (m, 2H), 3.64 (ddt, J = 15,0, 10.2, 5.1 Hz, 2H), 4,08 (dd, J = 9.2, 7, 1 Hz, IH), 5.52 (s, IH), 6.63 (q, J = 6.8 Hz, IH), 7.26 (m, 4H), 7.43 (dd, J - 8.5, 2.3 Hz, IH), 7.66 (d, J = 8.5 Hz, IH)
be ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, IH), 1.58 (m, 4H), 1.99 (dd, J = 13.3, 7.1 Hz, IH), 2.27 (dd, J = 13.3, 9, 1 Hz, IH), 2.42 (s, 3H), 3.01 (d, J = 11.6 Hz, IH), 3.19 (d, J = 11.5 Hz, IH), 3.47 (ddt, J = 21.2, 13.6, 6.9 Hz, 2H), 3.64 (dq, J = 12.3, 5.8 Hz, 2H), 3.98 (dd, J = 9.1, 7.1 Hz, IH), 5.52 (s, IH), 6.61 (q, J = 6.8 Hz, IH), 7.18 (s, IH), 7.31 (m, 3H), 7.46 (dd, J = 8.5, 2,3 Hz, IH), 7.68 (d, J = 8.3 Hz, IH)
bf Ή NMR (400 MHz, MeOH-d4): δ ppm 0.89 (t, J = 6.6 Hz, IH), 1.29 (d, J = 7.9 Hz, 4H), 1.62 (s, 8H), 2.09 (d, J - 6.9 Hz, IH), 2.34 (t, J = 10.9 Hz, 2H), 3.15 (d, J = 8.2 Hz, 2H), 3.25 (m, IH), 3.32 (s, 2H), 3.48 (s, 4H), 3.54 (s, IH), 3.66 (s, 5H), 4.12 (s, 2H), 5.56 (s, IH), 6.60 (q, J - 6,7 Hz, 2H), 7.34 (m, 5H), 7.50 (dd, J = 8.6, 2.2 Hz, 2H), 7.68 (d, J = 8.5 Hz, 2H)
bg Ή NMR (400 MHz, MeOH-d4): δ ppm 0.89 (m, 2H), 1 ,30 (d, J = 14.2 Hz, 7H), 1.61 (s, 12H), 2.07 (m, 3H), 2.36 (dd, J = 13.3, 8.3 Hz, 3H), 2.80 (s, IH), 3.15 (d, J = 1 1.8 Hz, 3H), 3.26 (d, J = 1 1.5 Hz, 3H), 3.46 (d, J = 16.1 Hz, 5Η), 3.52 (d, J = 7.0 Hz, 2Η), 3.64 (s, 7H), 4.18 (s, 3H), 4.92 (s, IH), 4.98 (s, IH), 6.58 (q, J = 6.7 Hz, 3H), 7.33 (d, J = 2.0 Hz, 3H), 7.47 (m, 12H), 7.67 (m, 6H)
bh Ή NMR (400 MHz, MeOH-d4): δ ppm 0.89 (t, J = 6.4 Hz, IH), 1.29 (d, J = 4.7 Hz, 2H), 1.62 (q, J = 6.3, 5.4 Hz, 4H), 2.07 (dd, J = 13.4, 7.3 Hz, IH), 2.36 (dd, J = 13.5, 9.1 Hz, HI), 3.15 (d, J = 11.8 Hz, IH), 3.26 (m, IH), 3.50 (ddd, J = 20.3, 10.5, 6.5 Hz, 2H), 3.65 (m, 2H), 4.16 (t, J = 8.2 Hz, IH), 4.68 (s, IH), 4.95 (t, J = 1 1 ,4 Hz, IH), 6.40 (q, J = 6.5 Hz, IH), 7.41 (d, J = 2.2 Hz, IH), 7.56 (dd, J = 8.5, 2.3 Hz, IH), 7.71 (d, J = 8.6 Hz, IH), 8.12 (s, 3H)
bi ¾ NMR 400 MHz, MeOH-d4): δ ppm 0.89 (d, J = 6.7 Hz, IH), 1.15 (s, IH), 1.28 (m, 9H), 1.57 (d, J = 6.4 Hz, 5H), 1.92 (dt, J = 13.9, 6.8 Hz, IH), 2.21 (dd, J = 13.2, 9.1 Hz, IH), 2.95 (in, 2H), 3.11 (d, J = 11 A Hz, IH), 3.44 (ddt, J = 20.6, 13.0, 6.2 Hz, 2H), 3.60 (dd, J = 13.8, 6.6 Hz, 2H); 3.87 (dd, J = 9,0, 7.0 Hz, IH), 5.46 (s, IH), 6.61 (q, J = 6.8 Hz, IH), 7.39 (m, 6H), 7,66 (d, J = 8.5 Hz, IH)
bj ¾ NMR400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 5.0 Hz, 3H), 1.55 (m, 6H), 1.82 (dd, J - 12.9, 6.9 Hz, IH), 2, 10 (dd, J = 13.0, 9.0 Hz, IH), 2.71 (d, J = 1 1.1 Hz, IH), 3.00 (d, J = 1 1.1 Hz, IH), 3.32 (s, 3H), 3.45 (tt, J = 13.0, 6.3 Hz, 3H), 3,65 (ddd, J = 18.3, 10.9, 7,1 Hz, 4H), 4.88 (s, 17H), 5.53 (s, 2H), 6.54 (q, J = 6.6 Hz, I H), 7,32 (d, J = 2.3 Hz, IH), 7.51 (m, 5H), 7.59 (t, J = 1.9 Hz, IH), 7.70 (d, J = 8.5 Hz, IH)
bk Ή NMR (400 MHz, MeOH-d4): δ ppml .28 (s, IH), 1.62 (q, J = 5.5 Hz, 4H), 2.07 (dd, J = 13.5, 7.3 Hz, IH), 2.35 (dd, J = 13.6, 9.1 Hz, IH), 3,15 (d, J = 1 1.8 Hz, IH), 3,26 (d, J = 11.7 Hz, IH), 3.49 (ddt, J = 21.5, 14.0, 6.1 Hz, 2H), 3.65 (m, 2H), 4, 15 (dd, J = 9, 1, .4 Hz, IH), 6.49 (q, J = 6.6 Hz, I H), 7.34 (d, J = 2.2 Hz, IH), 7.52 (m, 2H), 7.68 (d, J = 8.5 Hz, IH), 7.81 (s, 2H)
bl Ή NMR (400 MHz, MeOH-d4): δ ppm 1.33 (m, 8H), 1.56 (q, J = 5.9, 5.2 Hz, 4H), 1.89 (dd, J = 13.1, 7.0 Hz, IH), 2.18 (dd, J = 13.1, 9.0 Hz, IH), 2.86 (d, J = 11 ,3 Hz, IH), 3.08 (d, J = 1 1.4 Hz, IH), 3.46 (ddd, J = 15,1, 12.2, 6.6 Hz, 2H), 3.61 (dd, J = 13,4, 6.0 Hz, 2H), 3.82 (dd, J = 9.0, 7.0 Hz, IH), 4.68 (hept, J = 6.0 Hz, IH), 5.51 (s, IH), 6.72 (q, J = 8.2, 7.0 Hz, 2H), 6.82 (dt, J = 11.1 , 2.3 Hz, IH), 7.02 (s, IH), 7.28 (d, J = 2.2 Hz, IH), 7.44 (dd, J = 8.5, 2.3 Hz, IH), 7.67 (d, J = 8.6 Hz, IH)
bm !H NMR (400 MHz, MeOH-d4): δ ppml.32 (d, J = 18.8 Hz, 11H), 1.60 (q, J - 5,8 Hz, 4H), 2.05 (dd, J = 13.5, 7.2 Hz, IH), 2.33 (m, 2H), 2.43 (s, 3H), 3.12 (d, J = 11.7 Hz, IH), 3.25 (d, J = 11.7 Hz, IH), 3.45 (ddt, J = 21.7, 13.4, 6.5 Hz, 2H), 3.62 (dq, J = 11.4, 5.5 Hz, 2H), 4,09 (dd, J = 9.2, 7.2 Hz, IH), 6.64 (q, J = 6.8 Hz, IH), 7.05 (s, IH), 7.26 (m, 2H), 7.34 (d, J = 1.8 Hz, IH), 7.42 (dd, J = 8.5, 2.3 Hz, IH), 7.66 (d, J = 8.5 Hz, IH)bm ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 2H), 1.53 (t, J = 6.1 Hz, 4H), 1.80 (dd, J = 13.0, 6.9 Hz, IH), 2.09 (dd, J - 13,0, 8.9 Hz, IH), 2.36 (d, J = 2.0 Hz, 3H), 2.68 (d, J = 10.8 Hz, IH), 2.98 (d, J = 1 1.1 Hz, IH), 3.42 (m, 2H), 3.63 (m, 3H), 5.49 (s, IH), 6.64 (q, J = 6.8 Hz, IH), 7.24 (m, 3H), 7.43 (m, 2H), 7.67 (d, J = 8.5 Hz, IH)
bo IH NMR (400 MHz, MeOH-d4): δ ppm 1.30 (d, J = 13.0 Hz, IH), 1.53 (m, 4H), 1.79 (dd, J = 12.9, 6.9 Hz, IH), 2.08 (dd, J = 12.9, 8.9 Hz, IH), 2.66 (d, J = 11.1 Hz, IH), 2.97 (d, J = 11.0 Hz, IH), 3.42 (m, 3H), 3.62 (m, 3H), 5.50 (d, J = 15.0 Hz, IH), 6.53 (q, J = 6.9 Hz, IH), 7,36 (d, J = 2.3 Hz, IH), 7.53 (dd, J = 8.4, 2,2 Hz, IH), 7.63 (dd, J = 8,0, 5.0 Hz, IH), 7.72 (d, J = 8.5 Hz, IH), 7.98 (m, IH), 8.67 (m, IH), 8.74 (s, IH)
bp Ή NMR (400 MHz, MeOH-d4): δ ppm 1.41 (t, J = 6.9 Hz, 3H), 1.65 (dt, J = 10.9, 5.8 Hz, 4H), 2.08 (dd, J = 13.6, 8.2 Hz, IH), 2.44 (dd, J = 13.6, 8.9 Hz, IH), 3.24 (m, 2H), 4202
Figure imgf000195_0001
,—
IH)
bz ]H NMR (400 MHz, MeOH-d4): δ ppm 1.02 (m, 7H), 1.28 (d, J = 5.2 Hz, IH), 1.60 (q, J = 6.1 , 5.6 Hz, 4H), 2.06 (ddt, J = 14.1, 1 1.3, 6.7 Hz, 2H), 2.33 (dd, J = 13.4, 9.2 Hz, IH), 3.12 (d, J = 11.7 Hz, IH), 3.27 (d, J = 25.3 Hz, 3H), 3.47 (ddt, J = 20.4, 13, 1 , 5.7 Hz, 2H), 3,65 (m, 2H), 3.81 (m, 2H), 4.08 (dd, J = 9.1, 7,3 Hz, IH), 5.51 (s, IH), 6.71 (q, J = 6.8 Hz, I H), 7.01 (m, 2H), 7.18 (s, IH), 7.29 (d, J = 2.1 Hz, IH), 7.43 (m, 2H), 7.66 (d, J = 8.6 Hz, IH)
ca Ή NMR (400 MHz, MeOH-d4); δ ppm 1.00 (t, J = 7.3 Hz, IH), 1.28 (m, IH), 1.60 (m, 5H), 1.97 (m, 5H), 2.30 (t, J = 1 1.2 Hz, IH), 2.83 (t, J = 7.4 Hz, 1 H), 3.07 (d, J = 11.5 Hz, IH), 3.22 (d, J = 1 1.4 Hz, IH), 3.54 (m, 8H), 4.04 (d, J = 8.7 Hz, IH), 5.08 (s, IH), 5.56 (s, IH), 6.69 (q, J = 6.6 Hz, IH), 7, 1 (d, J = 2.1 Hz, IH), 7.48 (m, 2H), 7.65 (m, 3H), 7,93 (s, IH)
cb !H NMR (400 MHz, MeOH-d4): δ ppm 1 ,29 (m, IH), 1.62 (m, 6H), 1.90 (m, 8H), 2.32 (dd, J = 13,4, 9,1 Hz, IH), 3.1 1 (d, J = 11.7 Hz, IH), 3.25 (d, J = 11.6 Hz, IH), 3.47 (ddt, J = 21.4, 13.3, 6.4 Hz, 2H), 3.65 (dq, J = 13,0, 6.2 Hz, 2H), 4.08 (dd, J = 9.1, 7.1 Hz, IH), 5.51 (s, IH), 6.72 (q, J = 6,9 Hz, IH), 6.94 (d, J = 7,7 Hz, IH), 7.02 (dd, J = 8.2, 2,6 Hz, IH), 7.18 (s, IH), 7.28 (d, J = 2.3 Hz, IH), 7.42 (m, 2H), 7.66 (d, J = 8.5 Hz, IH)cc Ή NMR (400 MHz, MeOH-d4): δ ppm 1.29 (m, IH), 1.49 (m, 8H), 2.02 (m, 5H), 2.33 (dd, J = 13.3, 9.0 Hz, IH), 3.13 (d, J = 1 1.6 Hz, IH), 3.25 (d, J = 12.3 Hz, IH), 3,58 (ddd, J = 32, 1 , 26.0, 15.3 Hz, 5H), 3,88 (td, J = 10.6, 10.2, 3.9 Hz, IH), 4.08 (t, J = 8.1 Hz, IH), 5.56 (s, IH), 6.63 (q, J = 6.7 Hz, IH), 7.29 (d, J = 2.2 Hz, IH), 7.56 (m, 4H), 7,89 (d, J = 7.7 Hz, IH), 8.34 (s, IH)
cd ¾ NMR (400 MHz, MeOH-d4): δ ρρ'" 1.28 (q, J = 7.6, 6,7 Hz, 4H), 1.57 (p, J = 3,8 Hz, 4H), 1.99 (dd, J = 13.3, 7.1 Hz, IH), 2.27 (dd, J = 13.3, 9.1 Hz, IH), 2.73 (q, J = 7.6 Hz, 2H), 3.01 (d, J = 11.5 Hz, IH), 3.18 (d, J = 11.6 Hz, H), 3.45 (ddt, J = 21.2, 13.1, 5.9 Hz, 2H), 3.60 (dt, J = 12.5, 6.8 Hz, 2H), 3.98 (dd, J = 9.1, 7.1 Hz, IH), 4.93 (s, 1 IH), 5.47 (s, IH), 6.64 (q, J = 6.8 Hz, IH), 7.30 (m, 4H), 7.43 (m, 2H), 7.66 (d, J = 8.5 Hz, IH)
ce ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.28 (m, 9H)} 1 ,52 (ddd, J 11 ,5, 7.0, 4.8 Hz, 4H), 1.74 (dd, J = 13.1, 7.2 Hz, IH), 2, 10 (dd, J = 13.1, 8.8 Hz, IH), 2.75 (d, J = 10,9 Hz, IH), 2.95 (m, 2H), 3.50 (m, 4H), 3.83 (dd, J = 8.8, 7.2 Hz, IH), 4.18 (qd, J = 7.1, 1 ,5 Hz, 2H), 4.92 (s, 8H), 5.47 (d, J = 14.2 Hz, IH), 6.61 (q, J = 6.8 Hz, IH), 7.32 (m, 4H), 7.44 (m, 2H), 7,66 (d, J = 8.5 Hz, IH)
cf Ή NMR (400 MHz, MeOH-d4): δ ppm 0.09 (s, OH), 0.89 (t, J = 6.5 Hz, OH), 1.31 (d, J = 12.8 Hz, IH), 1.59 (m, 0H)} 1.84 (s, OH), 2.02 (d, J = 6.4 Hz, OH), 2.19 (t, J = 7,8 Hz, OH), 2.65 (s, OH), 2.76 (t, J = 6.7 Hz, OH), 2.87 (d, J = 14.6 Hz, OH), 3,06 (s, OH), 3.30 (s, IH), 3.49 (m, OH), 3.61 (m, OH), 3.82 (s, OH), 4,98 (s, OH), 5.33 (m, OH), 5.55 (s, OH), 7.30 (s, OH), 7.38 (d, J = 7.9 Hz, OH), 7.46 (t, J = 7.3 Hz, OH), 7.54 (t, J = 7.8 Hz, OH), 7.64 (m, OH), 7.81 (t, J = 8.6 Hz, OH), 7.93 (m, OH), 8.40 (s, OH)
cg 'H NMR (400 MHz, MeOH-d4): δ pm 1.73 (p, J = 7,2, 6.3 Hz, 4H), 2.10 (dd, J = 13.7, 8,5 Hz, IH), 2.50 (dd, J = 13.6, 8.9 Hz, IH), 3.26 (m, 4H), 3.61 (m, 1 1 H), 3.78 (d, J = 16.7 Hz, 4H), 4.53 (t, J = 8.7 Hz, IH), 6.61 (m, IH), 7.36 (d, J = 2.2 Hz, IH), 7.58 (m, 6H)
ch Ή NMR (400 MHz, DMS0-d6): δ ppm 1.43 (m, 4H), 1.79 (dd, J = 13.3, 7.5 Hz, IH), 2.13 (m, IH), 2.30 (s, 3H), 2.48 (m, 3H), 2.95 (d, J = 11.8 Hz, IH), 3.09 (m, IH), 3.38 (s, IH), 3.44 (s, 6H), 3.66 (s, 2H), 3.82 (t, J = 8.3 Hz, IH), 5.54 (s, IH), 6.57 (q, J = 6.8 Hz, IH), 7.34 (d, J = 2.1 Hz, IH), 7.55 (m, 6H)
ci !H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J = 4.2 Hz, 2H), 1.59 (m, 5H), 1.99 (dd, J = 13.4, 6.9 Hz, IH), 2.27 (dd, J = 13.3, 8.9 Hz, IH), 2.80 (s, 3H), 3.01 (d, J = 1 1.5 Hz, IH), 3.18 (d, J = 1 1.4 Hz, IH), 3.48 (m, 3H), 3.62 (q, J = 6.8, 5.6 Hz, 2H), 3.98 (t, J = 8.0 Hz, IH), 5.52 (s, IH), 6.75 (q, J - 6.7 Hz, IH), 7.49 (m, 3H), 7.69 (d, J = 8.5 Hz, IH), 7.76 (s, IH)
cj Ή NMR (400 MHz, MeOH-d4): δ ppm 1.29 (m, IH), 1.58 (s, 8H), 2.06 (dd, J = 10.2, 6.4 Hz, 2H), 2.30 (m, 2H), 3.12 (s, 2H), 3.23 (d, J = 9.6 Hz, 2H), 3.49 (m, 4H), 3.64 (s, 9H), 4.07 (t, J - 7.9 Hz, 2H), 5.64 (s, IH), 6.24 (d, J = 7.2 Hz, 2H), 6.50 (t, J = 6.8 Hz, 2H), 7.31 (d, J = 2.2 Hz, 2H), 7.46 (dd, J - 14.7, 7.7 Hz, 3H), 7.65 (d, J = 8.5 Hz, 2H), 7.78 (dd, J = 12.8, 6.1 Hz, 2H)
ck 'H NMR (400 MHz, MeOH-d4): δ ppm 1.62 (q, J = 6.1, 5.6 Hz, 4H), 2.06 (dd, J = 13.4, 7.2 Hz, IH), 2.34 (dd, J = 13.5, 9.2 Hz, IH), 2.58 (s, 3H), 3.13 (d, J = 1 1.7 Hz, IH), 3.26 (d, J = 1 1.7 Hz, 2H), 3.51 (m, 2H), 3.68 (td, J = 14.8, 14.3, 7.0 Hz, 2H), 4.08 (dd, J = 9.2, 7.1 Hz, IH), 4.87 (d, J = 7.3 Hz, IH), 4.97 (s, IH), 5.60 (s, IH), 6.65 (q, J = 6.6 Hz, IH), 7.34 (d, J = 2.3 Hz, IH), 7.50 (dd, J = 8.6, 2.2 Hz, IH), 7.67 (dd, J = 12.0, 8.0 Hz, 2H), 7.77 (t, J = 7.8 Hz, HI), 7.94 (dt, J = 7.9, 1.4 Hz, IH), 8.31 (s, IH)
cl 'H NMR (400 MHz, MeOH-d4): δ ppm 1.61 (d, J = 5.5 Hz, 5H), 2.04 (dd, J = 13.3, 7.1 Hz, IH), 2.31 (dd, J = 13.4, 9.2 Hz, IH), 2.73 (s, 6H), 3.08 (d, J = 11.6 Hz, IH), 3.23 (d, J = 11.7 Hz, IH), 3.53 (m, 2H), 3.68 (d, J = 14.2 Hz, 2H), 4.04 (dd, J = 9.1, 7.0 Hz, IH), 5.62 (s, IH), 6.69 (q, J = 6.6 Hz, IH), 7.36 (d, J = 2.3 Hz, IH), 7.50 (dd, J = 8.5, 2.3 Hz, IH), 7.70 (dd, J = 12.4, 7.7 Hz, 2H), 7.86 (m, 2H), 8.33 (s, IH)
cm 'H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (s, IH), 1.57 (p, J = 7.6, 6.8 Hz, 4H), 1.86 (dd, J = 13.0, 6.9 Hz, IH), 2.15 (dd, J - 13.2, 9.0 Hz, IH), 2.81 (d, J = 11.2 Hz, IH), 2.95 (s, 4H), 3.05 (d, J = 1 1.2 Hz, IH), 3.32 (s, IH), 3.46 (ddt, J = 17.4, 13.1 , 5.7 Hz, 2H), 3.62 (dq, J = 11.5, 5.5 Hz, 2H), 3.76 (dd, J - 9.0, 6.9 Hz, IH), 5.54 (s, IH), 6.63 (q, J - 6.7 Hz, IH), 7.29 (d, J = 2.3 Hz, IH), 7.46 (dd, J = 8.5, 2.3 Hz, IH), 7.62 (m, 3H), 7.89 (dt, J = 7.7, 1.5 Hz, IH), 8.36 (s, IH)
cn Ή NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 2H), 1.62 (q, J = 5.7, 5.0 Hz, 12H), 2.07 (dd, J = 13.4, 7.1 Hz, 3H), 2.35 (dd, J = 13.4, 9.1 Hz, 3H), 3.09 (d, J = 26.8 Hz, 23H), 3.26 (s, 2H), 3.53 (m, 6H), 3.64 (d, J = 13.0 Hz, 7H), 4.15 (s, 3H), 4.88 (d, J = 3.3 Hz, IH), 4.97 (s, IH), 5.56 (s, IH), 6.71 (q, J = 6.7 Hz, 3H), 7.32 (d, J = 2.2 Hz, 3H), 7.56 (m, 15H), 7.78 (s, 3H)
co 'H NMR (400 MHz, MeOH-d4): δ ppm 1.13 (t, J = 7.1 Hz, 3H), 1.26 (m, 4H), 1.61 (q, J = 6.1, 5.6 Hz, 4H), 2.05 (dd, J = 13.4, 7.2 Hz, IH), 2.33 (dd, J = 13.4, 9.3 Hz, IH), 3.13 (d, J = 11.7 Hz, IH), 3.47 (m, 10H), 4.09 (t, J = 8.3 Hz, IH), 5.55 (s, IH), 6.74 (q, J = 6.8 Hz, III), 7.32 (d, J = 2.2 Hz, IH), 7.48 (m, 3H), 7.65 (m, 3H)
cp 'H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (m, 7H), 1.58 (d, J = 13.6 Hz, 14H), 2.05 (m, 3H), 2.31 (s, 4H), 2.88 (s, IH), 3.11 (d, J = 12.1 Hz, 3H), 3.25 (d, J = 12.8 Hz, 3H), 3.38 (s, 10H), 3.48 (s, 3H), 3.63 (m, 5H), 4.09 (t, J = 8.2 Hz, 3H), 4.48 (s, 2H), 4.98 (s, 3H), 5.10 (s, IH), 5.42 (s, 2H), 5.54 (s, 2H), 6.50 (d, J = 13.3 Hz, 2H), 6.79 (m, IH), 7.22 (s, 2H), 7.44 (s, 5H), 7.53 (d, J = 8.4 Hz, 5H), 7,76 (s, 7H), 8.11 (m, 3H)
cq 'H NMR (400 MHz, MeOH-d4): δ ppm 1.31 (s, 3H), 1.62 (s, 8H), 2.08 (dd, J = 13.3, 7.1 Hz, 2H), 2.35 (t, J = 11.4 Hz, 2H), 3.16 (d, J = 11.8 Hz, 2H), 3.32 (m, 23H), 3.49 (s, 4H), 3.63 (d, J = 19.6 Hz, 3H), 3.83 (s, 4H), 3.90 (s, 2H), 3.97 (s, 2H), 4.05 (s, IH), 4.13 (t, J = 7.7 Hz, 2H), 6.67 (m, 2H), 7.35 (s, 2H), 7.51 (d, J = 8.7 Hz, 2H), 7.66 (dq, J = 31.2, 9.5, 9.1 Hz, 7H), 7.84 (s, 2H)
4cr Ή NMR (400 MHz, MeOH-d4): δ ppm 0.46 (m, 4H), 1.28 (s, IH), 1.58 (s, 4H)5 1.69 (d, J = 7.3 Hz, 1H)} 1.97 (d, J = 9.1 Hz, IH), 2.24 (dd, J = 13.1, 9.0 Hz, 1H), 2.58 (s, 2H), 2.73 (s, 2H); 2.96 (d, J = 11.3 Hz, IH), 3.15 (d, J = 1 1.6 Hz, IH), 3.32 (m, IH), 3.48 (t, J = 12.1 Hz, 4H), 3.63 (s, 2H), 3.76 (s, 2H), 3.92 (t, J = 8.1 Hz, IH), 5.55 (s, IH), 6.71 (q, J = 6.7 Hz, IH), 7.33 (d, J = 2.2 Hz, IH), 7.50 (m, 3H), 7.66 (m, 2H), 7.80 (s, IH)
4cl *H NMR (400 MHz, MeOH-d4): δ ppm 8.71 (d, J = 4.7 Hz, IH), 8.02 (t, J = 7.9 Hz, IH), 7.72 (t, J = 7.3 Hz, 2I-I), 7.52 (d, J = 10.9 Hz, 3H), 6.92 (d, J = 6.7 Hz, IH), 5,87 (s, IH), 4.80 (s, 7H), 4.10 (d, J = 8.7 Hz, IH), 3.66 (s, 2H), 3.50 (s, 2H), 3.30 (s, 5H), 3.25 (d, J = 11.8 Hz, IH), 3.12 (d, J = 11.7 Hz, IH), 2.35 - 2.27 (m, IH), 2.06 (dd, J = 13.3, 7.1 Hz, IH), 1.59 (s, 3H), 1.59 (d, J = 11.4 Hz, IH)
34cm Ή NMR (400 MHz, MeOH-d4): δ ppm 8.99 (d, J = 4.9 Hz, 2H), 8.03 (s, H), 7.75 (d, J = 9.4 Hz, 2H), 7.60 - 7.49 (m, 2H), 5.71 (s, IH), 4.10 (s, IH), 3.59 (d, J = 18.5 Hz, 2H), 3.30 (d, J = 3.1 Hz, 9H), 3.11 (d, J = 12.0 Hz, 1H), 2.31 (t, J = 11.6 Hz, IH), 2.06 (s, IH), 1.57 (s, 5H), 1.28 (s, IH)
34cu ¾ NMR (400 MHz, MeOH-d4): δ ppm 8.96 (d, J = 1.5 Hz, IH), 8.83 - 8.77 (m, IH), 8.71 (d, J = 2.6 Hz, IH), 7.77 (d, J = 8.4 Hz, IH), 7.64 - 7.55 (m, 2H), 6.87 (q, J = 6.7 Hz, 1H), 5.64 (s, 1H), 3,99 (t, J = 8.2 Hz, lH), 3.46 (s, IH), 3.19 (d, J = 11.6 Hz, IH), 3.03 (d, J = 1 1.6 Hz, IH), 2.27 (dd, J = 13.3, 9.2 Hz, IH), 2.00 (dd, J = 13.4, 7.0 Hz, IH), 1.57 (s, 3H), 1.29 (s, IH).
34cv ¾ NMR (400 MHz, MeOH-d4): δ ppm 7.67 (d, J = 8.5 Hz, 2H), 7.44 (ddd, J = 8.0, 4.8, 2.6 Hz, 3H), 7.32 - 7.23 (m, 3H), 7.07 (dd, J = 8.4, 2.6 Hz, 2H), 6.98 (d, J = 7.6 Hz, IH), 6.76 (d, J = 7.0 Hz, 2H), 4.26 - 4.05 (m, 5H), 3.75 (t, J = 4.7 Hz, 3H), 3.42 (s, 4H), 3.36 (s, IH), 3.26 (d, J = 1 1.7 Hz, 3H), 3.13 (d, J = 11.7 Hz, 2H), 2.33 (dd, J = 13.5, 9.1 Hz, 2H), 2.06 (dd, J = 13.4, 7.1 Hz, 2H), 1.61 (d, J = 5.6 Hz, 5H).
Example 35: (S)-8-(2-ammo-6-((R)-l-(5-chloro-3'-(ethoxycarbonyl)-[l,l'-biphcnyl]-2-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]dccane-3-carboxylic acid
Figure imgf000198_0001
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-l-(2'-(ethoxycarbonyl)- 4-(3-methyl-lH-pyrazol-l-yl)-[l,l'-biphenyl]-3-yl)-2,2,2-ttifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid (Example 20) starting with (S)-8-(2-amino-6-((R)-l-(2- bromo-4-chlorophenyl)-2,2,2-trifiuoiOethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8- diazaspiro [4.5 ]decane- 3 - carboxy 1 ic acid . 1H NMR (400 MHz, DMSO-d6): δ ppm 1.29 - 1.38 (m, 3 H) 1.47 - 1.72 (m, 4 H) 1.91 (dd, 1=13.28, 9.18 Hz, 1 H) 2.35 (dd, J=13.25, 8.61 Hz, 1 H) 3.14 (br. s., 2 H) 3.65 (br. s., 4 H) 4.30 - 4.40 (m, 2 H) 4.40 - 4.50 (m, 1 H) 5.90 (br. s., 1 H) 6.59 (q, J=6.67 Hz, 1 H) 7.1 1 (br. s., 1 H) 7.44 (t, J=1.22 Hz, 1 H) 7.66 (s, 2 H) 7.70 - 7.79 (m, 2 H) 8.08 (dt, J=6.37, 2.14 Hz, 1 H) 8.14 (br. s„ 1 H) 8.98 (d, J=5.61 Hz, 1 H) 10.36 (d, J=5,08 Hz, 1 H). LCMS (MH+): 634.
Example 36: (S)-8-(2-amino-6-((R)-l-(4-chloro-2-(2-methoxyet oxy)phenyl)-2,2,2- trifluoiOethoxy)pyrimidin- -yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000199_0001
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-l-(4-chloro-2-(3- methyl- lH-pyrazol- 1 -yl)phenyl)-2J2,2-trifluoiOethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid (Example lOd) starting with (R)-l-(4-bromo-2-(2- methoxyethoxy)phenyl)-2,2,2-trifluoroethanol and obtained as a white solid.
Ή NMR (400 MHz, DMSO-d6): δ ppm 1.44 - 1.66 (m, 4 H) 1.83 - 1.95 (m, 1 H) 2.34 (dd, J=13.08, 8.79 Hz, 1 H) 3.14 (br. s„ 2 H) 3.33 (s, 3 H) 3.42 - 3.65 (m, 4 H) 3.67 - 3.79 (m, 2 H) 4.19 - 4.27 (m, 1 H) 4.27 - 4.36 (m, 1 H) 4.48 (t, J=6.49 Hz, 1 H) 5.74 (s, 1 H) 6.99 (q, J=6.78 Hz, 1 H) 7.07 - 7.16 (m, 1 H) 7.27 (s, 1 H) 7.43 (d, J=8.35 Hz, 1 H) 8.93 (d, J=5.42 Hz, 1 H) 9.81 (br. s„ 1 H). LCMS (MH+): 560.
Example 36b: (S)-8-(6-((R)-l-(2-(lH-benzo[dl nidazol-l-yl)-4-chlorophcnyl)-2,2,2- trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000200_0001
Step J To a solution of (R)-l-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroemanol (1 g, 3.5 mmol) and lH-benzo[d]imidazole (408 mg, 3.5 mmol) in toluene (24 mL) was added sequentially, Cul (131 mg, 0.69 mmol), K2C03 (1.19 g, 8.63 mmol), and (lR,2R)-Nl,N2-dimethyicyclohexane- 1,2-diamine (1 6 mg, 1.38 mmol). The reaction mixture was purged with N and then heated at 130 °C in a sealed tube for 12 h. Afterward, the reaction was cooled to RT. The solid was removed by filtration and the filtrate was concentrated and purified by flash column (EtOAc in hexane = 0 to 50 %) to afford -(R)-l-(2-(lH-benzo[d]imidazol-l-yl)-4-chlorophenyl)-2,2,2- trifluoroethanol as a white solid.
Steps 2-5; The title compound was made as described for Example lOd (Steps 1-4) to provide a white solid.
1H NMR (400 MHz, DMSO~d6): δ ppm 1.59 (m, 4H), 2.05 (dt, J = 13.7, 6.9 Hz, 1H), 2.33 (dt, J = 14.5, 8.5 Hz, 1H), 3.13 (dd, J = 1 1.7, 7.6 Hz, 1H), 3.26 (m, 2H), 3.49 (m, 3H), 3.63 (m, 2H), 4.10 (q, J = 7.0, 5.2 Hz, 1H), 5.48 (d, J = 3.9 Hz, 1H), 6.43 (p, J = 6.4 Hz, 1H), 7.22 (dd, J = 7.8, 4.0 Hz, 1H), 7.38 (m, 2H), 7.61 (dd, J = 5.3, 2.2 Hz, 1H), 7.81 (m, 3H), 8.54 (s, 1H). LCMS (MH+): 603. Example 36c: (S)-8-(2-amino-6-((R)-l-(4-chloro-2-(lH-indazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000201_0001
The title compound was prepared as described for (S)-8-(6-((R)-l-(2-(lH-benzo[d]imidazol-l- yl)-4-chloi phenyl)-2,2,2 rifluoroethoxy)-2-ami
carboxylic acid (Example 36b) starting withlH-indazole and obtained as a white solid,
Ή NMR (400 MHz, DMSO-d6): δ ppm 1.57 (m, 5H), 2.05 (dd, J = 13.4, 7.1 Hz, 1H), 2.32 (dd, J = 13.5, 9.2 Hz, 1H), 3.12 (d, J = 1 1.7 Hz, 1H), 3.24 (d, J = 11.7 Hz, 1H), 3.52 (dddd, J = 44,5, 25.8, 14.0, 7.1 Hz, 5H), 4.13 (dd, J = 9.1 , 7.1 Hz, 1H), 4.92 (s, 1H), 6.68 (q, J = 6.5 Hz, 1H), 7.31 (t, J = 7.4 Hz, 1H), 7.46 (m, 2H), 7.72 (m, 5H), 8.39 (s, 1H). LCMS (MH+): 603.
Example 36d; (S)-8-(2-amino-6-((R)-l-(4-bromo-2-(piperazin-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000201_0002
Step 1 ; A mixture of 4-biOino-2-fluoiObenzoic acid (2 g, 9.1 mmol), benzyl piperazine-1- carboxylate (2.4 g, 10,9 mmol) and 2C03 (2.5 g} 18.26 mmol) in DMF (40 mL) was stirred at 150 °C for 36 h. The reaction was then cooled to RT and extracted with ethyl acetate, 3 N HC1, brine, dried over Na2S04, filtered and concentrated in vacuo to provide 2-(4-((benzyloxy) carbonyl)piperazin-l-yl)-4-bromobenzoic acid as yellow oil that was used without further purification. Step 2: To a mixture of 2-(4-((benzyloxy) carbonyl)piperazin-l -yl)-4-bi'omobenzoic acid (2 g, 9.1 mmol) in THF (20 mL) was added dropwise BH3/THF (1.0 M, 40 mL) at 0 °C. The mixture was refluxed for 2 h, then cooled to RT, quenched with H20, and extracted with ethyl acetate, 3 N HC1, brine, then dried ove Na2S04, filtered and concentrated. Purification by normal phase silica gel (ethyl acetate/hexanes) provided benzyl 4-(5-bromo-2- (hydroxyrnethyl)phenyl)piperazine-l-carboxylate as a white solid.
Steps 3-10: The title compound was prepared as described for (S)-8-(2-amino-6-((R)-2,2,2- trifluoro-l-(5-(methylsulfonyl)-[l,r-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2J8- diazaspiro[4.5]decane-3-carboxylic acid (Example 54d) following Steps 4-1 1. lU NMR (MeOH-d4): δ ppm 0.90 (dt, J = 16.0, 8.0 Hz, 1H), 1.31 (s, 2H); 1.62 (t, J = 5.6 Hz, 5H), 2.03 (dd, J = 13.6, .9 Hz, 1H), 2.30 (dd, J = 13.4, 9.1 Hz, 1H), 2.76 (dd, J = 10.1, 6.3 Hz, 2H), 3.08 (ra, 8H), 3.22 (d, J = 11.6 Hz, 1H), 3.47 (s, 1H), 3.54 (m, 1H), 3.65 (dd, J = 13.9, 6.8 Hz, 2H), 4.01 (t, J = 8.0 Hz, 1H), 5.56 (s, 1H), 7.31 (q, J = 6.9 Hz, 1H), 7.41 (dd, J = 8.4, 1.9 Hz, 1H), 7.50 (m, 2H). LCMS (MH+): 615.
Example 36e: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4'-isopropoxy-3-(piperazin-l-yl)- [l)l'-biphenyI]-4-yl)e hox )pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-cai*boxylic acid
Figure imgf000202_0001
The title compound was prepared starting with (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l -(2-(4- ((benzyloxy)carbonyl)piperazin-l-yl)-4-bromophenyl)-232,2-trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (intermediate from Step 8, Example 36d] via a Suzuki coupling with (4-isopropoxyphenyl)boronic acid as as described for example 54b, ¾ NMR (MeOH-d4): δ ppm 0.90 (m, IH), 1.33 (m, 8H), 1.40 (s, IH), 1.59 (q, J = 5.7 Hz, 4H), 2.06 (dd, J = 13,7, 7.0 Hz, IH), 2.31 (dd, J = 13,5, 9.2 Hz, IH), 3.1 1 (m, 3H), 3.26 (d, J = 1 1.7 Hz, IH), 3.51 (m, 10H), 4.09 (dd, J = 9.3, 6.8 Hz, IH), 4.64 (p, J = 6,0 Hz, IH), 5.56 (s, IH), 6.98 (m, 2H), 7.32 (q5 J = 7.0 Hz, IH), 7.53 (m, 4H), 7.64 (d, J = 8.2 Hz, IH). LCMS (MH+):
671.
Example 36f: (S)-8-(2-amiiio-6-((R)-2,2,2-trifluoiO-l-(4'-isopropoxy-3-niorpholino-[l,r- biphenyl]-4-yl)etho oxylic acid
Figure imgf000203_0001
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4'- ί sopropoxy- 3 - (piperazin- -y 1)- [ 1 , 1 '-bipheny 1]- 4-yl)ethoxy)py rimidin-4 -yl) -2, 8 - diazaspiro[4.5]decane-3-cafboxylic acid (Example 36e) substituting morpholine for benzyl piperazine- 1 -carboxylate. Ή NMR (MeOH-d4): δ ppm 1.32 (d, J = 6.0 Hz, 7H), 1.58 (d, J - 6.0 Hz, 4H), 1.98 (m, IH), 2.25 (dd, J = 13.3, 9.0 Hz, IH), 2.83 (m, 2H), 2.99 (d, J = 11.5 Hz, IH), 3.19 (m, 311), 3,32 (s, IH), 3,48 (ddt, J - 18.5, 8.9, 5,0 Hz, 2H), 3.62 (s, 2H), 3.92 (m, 5H), 4.63 (h, J = 6.0 Hz, IH), 4.88 (m, IH), 5.54 (s, IH), 6.97 (m, 2H), 7.41 (m, 2H)3 7.54 (m, 4H). LCMS (MH+): 672 Example 36g: (Si-S-ie-iiRi-l-dl^'-bi henyll^-ylJ^^^-trifluoroetho i^-amino pyrimidm-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxyIic acid
Figure imgf000204_0001
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-l-(5-chloi -3'- sulfamoyi-[l,r-biphenyl]-2-yl)-2,2,2-tiifluoroethoxy)pyrimidin-4-yl)--2,8-diazaspiiO[4.5]decane- 3-carboxylic acid (Example 34u) starting with l-(2-bromophenyl)-2J2)2-trifluoiOethanone.
Ή NMR (MeOH-d4): δ ppm 1.58 (d, J = 5.4 Hz, 4H), 2.00 (dd, J = 13.4, 7.1 Hz, 1H), 2.27 (dd, J = 13.3, 9.2 Hz, 1H), 3.02 (d, J = 1 1.6 Hz, 1H), 3.19 (d, J = 1 1.5 Hz, 1H), 3.30 (q, J = 1.8 Hz, 3H), 3.45 (td, J = 14.5, 6.3 Hz, 1H), 3.61 (m, 2H), 3.99 (m, 1H), 5.46 (s, 1 H), 6.67 (q, J = 6.8 Hz, 1H), 7.26 (dd, J = 6.2, 2.4 Hz, IH), 7.45 (m, 7H), 7.70 (d, J = 7.3 Hz, 1H). LCMS (MH+): 528.
Example 37: (3S)-8-(6-(l-((lr,3r,5S,7S)-adamantan-2-yl)ethoxy)-2-aminopyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000204_0002
Step 1: A solution of adamantan-l-yl-methanol (100 mg, 0.60 mmoi) in THF (5 mL) was cooled to 0 °C. 15-Cro n-5 ether (99 mg, 0.5 mmoi) and NaH (60% in oil, 92 mg, 2.4 mmoi) were added sequentially. The reaction was warmed to RT for 1 h, cooled to 0 °C, and 4,6-dichloro- pyrimidin-2-ylamine (247 mg, 1 ,5 mmoi) was added. The reaction was heated to 65 °C for 16 , cooled to RT, quenched with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. Purification by normal phase chromatography (EtO Ac/heptane) provided 4-(adamantan-l-ylmethoxy)-6-chloro- pyrimidin-2-ylamine as a white solid. Step 2: 4-(Adamantan-l-ylmethoxy)-6-chloro-pyrimidin-2-ylamine (89 mg, 0.30 mrnol), (S)-2- benzyl 3-ethyl 2,8-diazaspiro[4.53decane-2,3-dicarboxylate (157 mg, 0.45 mmol) and NaHC03 (76 mg, 0.9 mmol) were dissolved in dioxane (1.5 mL) and heated to 95 °C for 64 h. Then the reaction was cooled to RT, quenched with water, and extracted with EtOAc. The organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provides (S)-2-benzyl 3-ethyl 8-(6~(adamantan- 1 -ylmethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid. Step 3: N-CBZ Deprotection was accomplished via Method B to provide (S)-ethyl 8-(6-
(adamantan- 1 -ylmethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate as a white solid.
Step 4: Hydrolysis of (S)-ethyl 8-(6-(adamantan-l-ylmethoxy)-2-aminopyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxyiate using the LiOH general method provides the title compound as a white solid.
'H NMR (400 MHz, DMSO-d6): δ ppm 1.12 (d, J=6.25 Hz, 3 H) 1.42 - 1.76 (m, 17 H) 1 ,82 - 2.02 (m, 4 H) 2.34 (dd, J=13.32, 8.59 Hz, 1 H) 3, 12 (br. s., 2 H) 3.67 (br. s., 4 H) 4.35 - 4.48 (m, 1 H) 5.85 (br. s., 1 H) 8.97 (br. s., 1 H) 10.44 (br. s., 1 H). LCMS (MH+): 456.
Example 38; (S)-8-(6-((lr,3r,5S,7S)-adamantan-2-ylmethoxy)-2-aminopyrimi(lin-4-yl)-2)8- diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000205_0001
The title compound was made as described above for (3S)-8-(6-(l -((li',3r,5S,7S)-adamantan-2- yl)ethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid (Example 37) using (lr,3r,5rJ7r)-adamantan-2-ylmethanol.
Ή N R (400 MHz, DMSO-d6): δ ppm 1.39 - 1.76 (m, 16 H) 1.83 - 2.01 (m, 4 H) 2.34 (dd, J=13, 18, 8.44 Hz, 1 H) 3.13 (br. s„ 2 H) 3.69 (br. s., 4 H) 3.79 (s, 2 H) 4.42 (br. s., 1 H) 5.83 (b: s., 1 H) 8.97 (br. s., 1 H) 10.40 (br. s., 1 H). LCMS (MH+): 442,
Example 39a: 8-(4-Amino-6-((naphthalen-2-ylmethyl)amino)-l,3)5-triazin-2-yl)-2,8- diazaspiro [4.5] decane-3-carbox lic acid
Figure imgf000206_0001
Step 1: To a solution of 4,6-dichloi -l,3,5~triazin-2-amine (1.6 g) in isopropanol (14 mL) was added 2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2, 3-dicarboxylate (1.28 g, 3,7 mmol) and Et3N (7 mL). The solution was heated to reflux for 72 h, then cooled to RT, and concentrated in vacuo. Purification by normal phase chromatography (CPbCh/MeOH = 50/1 ) afforded 2-benzyl 3-ethyl 8-(4-amino-6-chloiO-l,3,5-triazin-2-yl)-2,8-diazaspii [4.5]decane-2,3-dicarboxylate as a colorless oil,
Step 2: To a solution of 2-benzyl 3-ethyl 8-(4-amino-6-chloro-l,3,5-triazin-2-yl)-2J8- diazaspiro[4.5]decane-2,3-dicai'boxylate (265 mg, 0.56 mmol) in isopropanol (3 mL) were added naphthalen-2-yImethanamine (105 mg, 0.67 mmol) and Et3N (1,4 mL). The reaction mixture was heated to reflux for 12 h, then cooled to RT, and concentrated in vacuo. Purification by normal phase chromatography (CH Ch/MeOH) provided 2-benzyl 3-ethyl 8-(4-amino-6- ((naphthalen-2-ylmethyl)amino)-l,3,5-triazin-2-yl)-2,8--diazaspiiO[4.5]decane-2,3-dicarboxylate as a white solid. Step 3: Hydrolysis of 2-benzyl 3-ethyl 8-(4-amino-6-((naphthalen-2-ylmethyl)amino)-l,3,5- triazin-2-yl)-2,8-diazaspii'o[4.5]decane-2,3-dicarboxylate using the LiOH general method provided 8-(4-amino-6-((naphthalen-2-ylmethyl)amino)- 1 ,3,5-triazin-2-yl)-2- ((benzyloxy)carbonyl)-2,8-diazaspii [4.5]decane-3-carboxylic acid as a white solid,
Step 4: N-CBZ Deprotection was accomplished via Method B to provide the title compound as a white solid.
Using the generic scheme below, the following examples of Table 13a were prepared as described above for 8-(4-amino-6-((naphthalen-2-ylmethyl)amino)-l,3,5-triazin-2-yl)-2,8- diazas
Figure imgf000207_0001
Table 13a.
Figure imgf000208_0001
Figure imgf000208_0002
Table 13b.
NMR Data for Compounds of Table 13a
Figure imgf000208_0003
Figure imgf000209_0001
Example 40: 8-(4-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yI)phenyl)-2,2,2- trifluoroethoxy)-l,3,5-triazin-2-yl)-2,8-diazaspiro[4,5]tlecane-3-carboxylic acid
Figure imgf000209_0002
Step 7: To a solution of (R)-l-(4-cbloiO-2-(3-methyl-lH-pyrazol-l-yl)phenyI)-2,2,2- trifluoroethanol (380 mg, 1.3 mmol) in 10 mL of THF was added NaH (60 mg, 1 ,4 mmol) and the reaction was stirred at RT for 30 min. After this time, 2-benzyl 3-ethyl 8-(4-amino-6-chloro- i ,3;5-triazin-2-yl)-2J8-diazaspiro[4.5]decane-2,3-dicarboxylate (product from Step 1, Example 39a) (570 mg, 1.2 mmol) was added and the reaction was heatd to 50 °C for 12 h, After this time, the reaction was cooled to RT, quenched with methanol and concentrated in vacuo.
Normal phase silica gel chromatography (EtOAc/heptane) provided 2-benzyl 3-ethyl 8-(4- amino-6-((R)-l-(4-chloi'o-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2-trifiuoiOethoxy)- 1,3,5- t['iazin-2-yl)-2,8-diazaspiro[4.5]decane-233-dicarboxylate as a white solid. Step 2: N-CBZ Deprotection was accomplished via Method B to provide ethyl 8-(4-amino-6-
((R)-l-(4-chloi -2-(3-methyl-lH-pyrazol-l -yl)phenyl)-2,2,2-trifIuoiOethoxy)-l}3,5-triazin-2-yl)- 2,8-diazaspii'o[4.5]decane-3-carboxylate as a white solid.
Step 3: Step 3: Hydrolysis of ethyl 8-(4-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l- yI)phenyl)-2,2,2-tdfluoroethoxy)-l,3,5-triazin-2-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate using the LiOH general method provided the title compound as a white solid. ]H NMR (400 MHz, MeOH-d4): 5 ppm 1.55 (br. s., 4 H) 1.98 (s, 1 H) 2.02 - 2.15 (m, 1 H) 2.30 (dd, J=13.42, 9.27 Hz, I H) 2.36 (s, 3 H) 3.10 (d, J=l 1.71 Hz, 1 H) 3.23 - 3.28 (m, 1 H) 3.40 - 4.01 (m,4 H) 4.08 (dd, J=9.27, 6.88 Hz, 1 H) 6.39 (d, J=2.25 Hz, 1 H) 7,36 - 7.63 (m, 3 H) 7.76 (d, J=8.54 Hz, 1 H) 7.91 (d, J=2.10 Hz, 1 H), LCMS (MH+): 567.
Example 41a: (S)-8-(2-Amino-6-((2-(piperidin-l-yl)benzyl)amino)pyrh-iidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxyIic acid
Figure imgf000210_0001
Step 1 : To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-chloropyrimidin-4-yl)-2,8-diazaspiiO [4.5]decane-2,3-dicarboxylate (200 mg, 0.6 mmol) and [2~(l-piperidinyl)phenyl]methanamine (CAS#: 72752-54-6) (105 mg, 0,8 mmol) in j-PrOH (2 mL) was added diisopropylethyl amine (0.5 mL). The reaction was heated to 120 °C for 2 h followed by heating to 140 °C for 1 h under microwave conditions, then cooled to RT and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((2-
(piperidin-1 -yl)benzyl)amino) pyrimidin-4-yl)-2f8-diazaspii'o[4.5]decane-2,3-dicarboxylate as a white solid,
Step 2: N-CBZ Deprotection was accomplished via Method B to provide (S)-ethyl 8-(2-amino-6- ((2-(piperidin- 1 -yl)benzyl)amino)pyrimidin-4-yl)-2,8-diazaspii [4,5]decane-3-carboxylate as a white solid.
Step 3: Hydrolysis of (S)-ethyl 8-(2-amino-6-((2-(pipei'idin-l-yl)benzyl)amino)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provided the title compound as a white solid. Using the generic scheme below, the following examples of Table 14a were prepared as described above for (S)-8-(2-amino-6-((2-(piperidin-l-yl)benzyl)amino)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid (Example 41a).
Figure imgf000211_0001
Figure imgf000211_0002
41d (3S)-8-(6-((l-((lR,3S,5S)-adamantan-l- 456
yl)ethyl)amino)-2-aminopyrimidin-4-yl)-2,8- diazaspiro [4.5 ]decane-3 -c arb oxy 1 ic aci d
Table 14b
NMR Data for Compounds of Table 14a
Figure imgf000212_0002
Example 42a: (SJ-S-f -amino-e-^RJ-l-iS'-chloro-Iljl'-bi hen ll- -yl)-!,!^- ti'ifluoroethoxy)pyrimidin-4- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000212_0001
The title compound was made as described for (S)-8-(2-amino-6-((R)-l-(5-chloro-3'- (ethoxycarbonyl)-[l ,r-biphenyI]-2-yl)-2,2,2-trifluoi'oethoxy)pynmidin-4-yl)-2)8- diazaspiiO[4.5]decane-3-carboxylic acid (Example 35) starting with (S)-2-benzyl 3-ethyl 8-(2- amino-6-((R)-l-(2-biOmophenyl)-2}2,2-trifluoiOethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5 ] decane-2,3 -dicarboxylate.
*H NMR (400 MHz, DMSO~d6): δ ppm 1.43 (h, J = 8.5, 6.5 Hz, 4H), 1.80 (dd, J = 13.3, 7.4 Hz, 1H), 2.12 (dd, J = 13.2, 9.0 Hz, 1H), 2.48 (d, J = 1.8 Hz, 1H), 2.95 (d, J = 11.7 Hz, 1H), 3.08 (d, J = 11.7 Hz, 1H), 3.37 (d, J = 16.1 Hz, 1H), 3.48 (d, J = 1 1.2 Hz, 3H), 3,79 (m, 2H), 5.57 (s, 1H), 6.62 (q, J - 6.9 Hz, 1H), 7.27 (dd, J = 5.8, 3.3 Hz, 1H), 7.51 (m, 7H). LCMS (MH+): 563.
Example 42b: (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(3,-fluoro-[l,l'-biphenyl]-2- yl)ethoxy)pyrimidin-4-yl)-2,8- iazaspiro[4.5]decane-3-carboxyIic acid
Figure imgf000213_0001
The title compound was made as described for (S)-8-(2-amino-6-((R)-l-(5-chloro-3'- (ethoxycarbonyl)-[l , 1 '-biphenyl]-2-yl)-2,2J2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid (Example 35) starting with (S)-2-benzyl 3 -ethyl 8-(2- amino-6-((R)-l-(2-biOmophenyl)-2,2J2-trifluoi ethoxy)pyrimidin-4-yl)-2,8- diazaspi ro [4.5] decane -2 , 3 -dicarboxylate .
Ή NMR (400 MHz, DMSO-d6): δ ppm 0.89 (m, 1H), 1.30 (d, J = 16.3 Hz, 3H), 1.60 (q, J = 5.9 Hz, 4H), 2.05 (dd, J = 13.4, 7.2 Hz, 1H), 2.32 (dd, J = 13.4, 9.1 Hz, 1H), 3.11 (d, J = 11.7 Hz, 1H), 3.24 (d, J = 11.7 Hz, 1H), 3.47 (ddt, J = 20.6, 1 .4, 6.5 Hz, 2H), 3.64 (ddt, J = 15.8, 10.8, 5.2 Hz, 2H)S 4.07 (dd, J = 9.2, 7.1 Hz, 1H), 5.51 (s, 1H), 6.68 (q, J = 6.9 Hz, 1H), 7.25 (m, 4H), 7.48 (m, 3H), 7.71 (m, 1H). LCMS (MH+): 546. Example 43: (S)-8-(5-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazoI-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyridazin-3-y!)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000214_0001
Step 1: To (R)-l-(4-chloi -2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2}2-tnfluoiOethanol (1.00 g, 3,44 mmol, Intermediate 3) in 1,4-dioxane (100 mL) was added 3,5-dichloropyridazine (512 mg, 3.44 mmol) and CS2CO3 (3.36 g, 10.3 mmol). The reaction mixture was then heated at 100°C for 182 h. During this time, the reaction was charged with additional 3,5-dichloropyridazine (2.56 g, 17.2 mmol) at t = 86 h. Then the reaction mixture was cooled to RT, diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuo. Purification on a 120 g Isco RediSep silica cartridge (EtO Ac/heptane) provided 3-chloi -5-[(lJ?)"l-[4-chloi -2-(3-methylpyrazol-l-yl)phenyl]-2,2,2- trifluoroethoxyjpy idazine as a 3:2 mixture of (R)-3-chloiO-5-(l-(4-chloro-2-(3-methyl-lH- pyrazol-l-yl)phenyl)-2,2,2-trifluoiOethoxy)pyridazine and (R)-5-chloro-3-(l-(4-chloro-2-(3- methyl- 1 H-pyrazol- 1 -yl)phenyl)-2,2J2-trifluoroethoxy)pyridazine respectively.
Step 2: To a solution of the (R)-3-chloro-5-(l-(4-chioro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)- 2)2,2-trifluoi ethoxy)pyridazine/(R)-5-chloro-3-(l-(4-chloiO-2-(3-methyI-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoiOethoxy)pyridazine mixture from step 1 in 1,4-dioxane (19 mL) was added 2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (980 mg, 2.83 mmol), Cs2C03 (2.30 g, 7.07 mmol), Pd2(dba)3 (432 mg, 0.471 mmol), and rac-BINAP (587 mg, 0.940 mmol), and the reaction mixture was heated to 60 °C for 60 h. Then the reaction mixture was cooled to RT, filtered through celite, washed with EtOAc, and the filtrate concentrated in vacuo. Purification on a 120 g Isco RediSep silica cartridge (EtOAc/heptane) provided (S)-2-benzyl 3- ethyl 8-(5-((R)- 1 -(4-chioro-2-(3-methyl- 1 H-pyrazol- 1 -yl)phenyl)-2,2,2- trifluoroethoxy)pyridazin-3-yl)-2,8-diazaspii [4,5]decane-2,3-dicarboxylate as a white solid. Step 3: N-CBZ Deprotection was accomplished via Method B to provide (S)-8-(5-((R)-l-(4- chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2)2-trifluoiOethoxy)pyridazin-3-yl)-3- (ethoxycarbonyl)-2J8-diazaspiro[4.5]decane-2-carboxylic acid as a white solid. Step 4: Hydrolysis of (S)-8-(5-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyridazin-3-yl)-3-(ethoxycarbonyl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid using the LiOH general method provided the title compound as an off-white solid.
'H NMR (400 MHz, MeOH-d4): δ ppm 1.66 - 1.80 (m, 4 H), 2.11 (dd, J = 13.45, 7.05 Hz, 1 H), 2.30 - 2.40 (m, 1 H), 2.36 (s, 3 H), 3.16 (d, J = 11.81 Hz, 1 H), 3.25 - 3.35 (m, 1 H), 3,37 - 3.65 (m, 4 H), 4.03 - 4.19 (m, 1 H), 6.39 (d, J = 2.34 Hz, 1 H), 6.63 (d, J = 2.39 Hz, 1 H), 6.95 (q, J = 6.39 Hz, 1 H), 7,43 - 7.57 (m, 2 H), 7.76 (d, J = 8.35 Hz, 1 H), 8,22 (d, J = 2.39 Hz, 1 H), 8.63 (d} J = 2,49 Hz, 1 H). LCMS (MH+): 551 Example 44: (S)-8-(4-((R)-2,2,2-trifluoro-l-(2-(3-methyl-lH-pyrazol-l- yl)plienyl)ethoxy)pyridi -2-yl)-2,8-tliazaspiro[4.5]decane-3-carboxylic acid
and
Example 45: (S)-8-(4-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyridin-2- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000215_0001
Step I To a solution of 2-chloro-4-nitropyridine (200 mg, 1.00 mmol) in 1,4-dioxane (6 mL) was added (R)-l-(4-chloiO-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2-trifiuoi ethanol (368 mg, 1.27 mmol), and Cs2C03 (828 mg, 2.54 mmol). The reaction was heated to 80 °C for 12 h, then cooled to RT, diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na S04, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (R)-2-chloiO-4-(l-(4-chloro-2-(3-methyl~lH-pyrazol-l- yl)phenyl)-2,2,2-trifmoiOethoxy)pyridine as an off-white solid.
Step 2: To a solution of (R)-2-chloro-4-(l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoiOethoxy)pyridine (227 mg, 0.57 mmol) in 1,4-dioxane (5 mL) was added 2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (237 mg, 0.68 mmol), Cs2C03 (557 mg, 1.71 mmol), BI AP (142 mg, 0,23 mmol), and Pd2(dba)3. The reaction was heated to 60 °C for 3 d, then cooled to RT, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided 2-benzyl 3-ethyl 8-(4-((R)-l-(4-chloro-2-(3-metnyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoiOethoxy)pyridin-2-yl)-2,8-diazaspiiO[4,5]decane-2,3-dicarboxylate as a white solid.
Step 3: Hydrolysis of 2-benzyl 3-ethyl 8-(4-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyridin-2-yl)-2,8-diazaspiiO[4.5]decane-2;3-dicarboxylate using the LiOH general method provided 2-((benzyloxy)carbonyl)-8-(4-((R)- 1 -(4-chloro-2-(3-methyl- lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoiOethoxy)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid.
Step 4: N-CBZ Deprotection was accomplished via Method A followed by normal phase silica gel purification (EtOAc: heptane) providing both of the title compounds as white solids (120 mg and 75 mg for the des-chloro analog).
8-(4-((R)-2,2,2-trifiuoiO- 1 -(2- (3 -methyl- 1 H-pyrazol- 1 -yl)phenyl)ethoxy)pyridin-2-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid:
¾ NMR (400 MHz, MeOH-d4): δ ppm 1.52 - 1.76 (m, 4 H) 1.95 - 2.15 (m, 1 H) 2.23 - 2.37 (m, 1 H) 2.39 (s, 3 H) 2.87 (s, 1 H) 3.05 - 3.16 (m, 1 H) 3.19 - 3.27 (m, 1 H) 3.38 - 3.72 (m, 4 H) 3.77 - 4.13 (m, 1 H) 6.39 (d, J=2.44 Hz, 1 H) 6.44 - 6.52 (m, 1 H) 6.79 (d, J=2,20 Hz, 1 H) 6,83 - 6.97 (m, 1 H) 7.43 - 7.51 (m, 1 H) 7.54 (d, J=2.05 Hz, 1 H) 7.66 (d, J=8.74 Hz, 1 H) 7.81 - 8.00 (m, 2 H). LCMS (MH+): 550. 8-(4-((R)-2,2,2-tnfluoro-l-(2-(3-methyl-lH-pyrazol-l-yl)phenyl)ethoxy)pyndin-2-yl)-2,8- diazaspiro[4.5 ] decane- 3 -carboxyl ic aci d :
Ή NMR (400 MHz, MeOH-d4): δ ppm 1.47 - 1.71 (m, 4 H) 1.95 - 2.04 (m, 1 H) 2.21 - 2.31 (m, 1 H) 2.39 (s, 3 H) 2.73 (s, 1 H) 3.02 (d, J=11.52 Hz, 1 H) 3.14 - 3.22 (m, 1 H) 3.37 - 4.03 (m, 4 H) 6.36 (d, J-2.34 Hz, i H) 6.43 - 6.51 (m, 1 H) 6.72 - 6.85 (m, 2 H) 7.30 - 7.51 (m, 3 H) 7.52 - 7.61 (m, 1 H) 7.67 (d, J=7.86 Hz, 1 H) 7.81 (d, J-2.34 Hz, 1 H) 7.86 - 7.91 (m, 1 H). LCMS (MH+): 516.
Example 46: 8-(4-((R)-l-(4-chloro-2-(3-methyI-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)-6-phenoxypyrinii(lin-2-yl)-2,8-diazaspii,o[4.5]tlecaiie-3-carboxyIic acid
Figure imgf000217_0001
Step 1; To a solution of 2-benzyl 3-ethyl 8-(4-chloro-6-((R)-l-(4-chloro-2-(3-methyl-lH- pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-2-yl)-2,8-diazaspii [4.5]decane-2,3- dicarboxylate (by-product from Step 3, Example 30a) (250 mg, 0.347 mmol) in 1 ,4-dioxane (9.0 mL) was added phenol (1 ,00 g, 10.6 mmol) and Cs2C03 (3.65 g, 1 1.2 mmol). The reaction was heated at 80°C for 12 h, then cooled to RT diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuo.
Purification on a 12 g Isco RediSep silica cartridge (EtO Ac/heptane) provided 2-benzyl 3-ethyl 8-(4-((R 1 -(4-chloro-2-(3-methyl- 1 H-pyrazol - 1 -yl)phenyl)-2,2,2-trifluoroethoxy 6- phenoxypyrimidin-2-yl)-2,8-diazaspiro[4.53decane-2,3-dicarboxylate as an off-white solid.
Step 2: N-CBZ Deprotection was accomplished via Method A to provide (ethyl 8-(4-((R)-l-(4- chioiO-2-(3-methyi-lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)-6-phenoxypyrimidin-2-yl)- 2,8-diazaspiro[4.5]decane-3-carboxylate as a white solid. Step 3: Hydrolysis of ethyl 8-(4-((R)-l-(4-chloiO-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoroethoxy)-6-phenoxypyrimidin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provided the title compound as an off-white solid. 'H NMR (400 MHz, MeOH-d4): 6 ppm 1.36 (br. s„ 4 H), 1.90 - 1.99 (m, 1 H), 2.1 1 - 2.21 (m; 1 H), 2.26 (s, 3 H), 2.92 - 3.17 (m, 2 H), 3.24 - 3.60 (m, 4 H), 3.96 (dd, J = 9.13, 6.88 Hz, 1 H), 5.44 (d, J = 2.29 Hz, 1 H), 6.27 - 6.33 (m, 1 H), 7.00 (d, J = 8.00 Hz, 2 H), 7.08 - 7.16 (m, 1 H), 7.24 - 7.32 (m, 2 H), 7.38 (dd, J = 8.44, 1.90 Hz, 1 H), 7.44 (d, J = 2.00 Hz, 1 H), 7.54 - 7.62 (m, 1 H), 7.64 (d, J = 8.49 Hz, 1 H), 7.81 (d, J = 2.25 Hz, 1 H). LCMS (MH+): 642.
Example 47: (3S)-8-(2-Amino-6-(l-(2,6-dibromoplieiiyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decan -3-carboxylic acid
Figure imgf000218_0001
The title compound was prepared as described for (S)~8-(2-amino-6-((R)-l -(4-chloro-2-(3- methyl- lH-pyrazol-l -yl)phenyl)-2,2,2-trifluoiOethoxy)pyrimidiii-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid (Example lOd) starting with l-(2,6-dibromophenyl)- 2,2,2-trifluoroethanol.
Ή NMR (400 MHz, MeOH-d4): δ ppm 1.29 (m, 1H), 1.62 (q, J = 5.7 Hz, 4H), 2.06 (m, 1H), 2.33 (dd, J = 13.5, 9.2 Hz, 1H), 3.13 (d, J = 11.7 Hz, 1H), 3.26 (d, J = 11.7 Hz, 1H), 3.49 (m, 2H), 3.65 (dq, J = 10.7, 5.4 Hz, 2H), 4.09 (dd, J = 9.2, 7.2 Hz, 1H), 5.56 (s, 1H), 7.15 (t, J = 8.0 Hz, 1H), 7.28 (q, J = 8.0 Hz, 1H), 7.69 (m, 2H). LCMS (MH+): 61 1.
Example 48: (S)-8-(2-Amino-6-((R)-l-(2,S-dibromophenyI)-2,2,2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000219_0001
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-l-(4-chloro-2-(3- methy 1 - 1 H-py razol - 1 -yl)phenyl) -2,2 ,2-tr ifluoroethoxy)pyr imidin-4 -y 1) -2, 8 - diazaspiro[4.5]decane-3-carboxylic acid (Example lOd) starting with l-(2,5-dibi mophenyl)- 2,2,2-trifluoroethanol.
!H NMR (400 MHz, MeOH-d4): 6 ppm 1.62 (q, J = 5.8, 5.2 Hz, 4H), 2.06 (dd, J = 13.5, 7.2 Hz, 1H), 2.34 (dd, J = 13.4, 9.2 Hz, 1H), 3.13 (d, J = 1 1.7 Hz, 1H), 3.26 (d, J = 1 1.8 Hz, 1H)5 3.50 (m, 2H), 3.66 (ddt, J = 15.0, 10.7, 5.2 Hz, 2H), 4,09 (dd, J = 9.2, 7.2 Hz, 1H), 4.83 (s, 1H), 5.58 (s, 1H), 6.97 (q, J - 6.6 Hz, 1H), 7.47 (dd, J = 8.6, 2.4 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H). LCMS (MH+): 611.
Example 49: (S)-8-(2-Amino-6-((R)-2,2ί2-trifluoΓO-l-(3'-(metll Isulfon l)-4- ro l-[l)l,- biphenyl]-2-yl)ethoxy)pyrimidi -4-yl)-2,8-diazaspiro[4,5]decane-3-carboxylic acid
Figure imgf000219_0002
Step 1: To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-l-(2-bromo-5-chloiOphenyl)- 2;2,2-trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-2J3-dicarboxylate (660 mg, 0.95 mmol) in dioxane (12 mL) was added (3-(methylsulfonyl)phenyl)boronic acid (285 mg, 1.43 rnmoi), Pd2(dppf)Cl2 (70 mg, 0.095 mmol) and Na2CO3(6.0 mL, 2.0 M, aq). The reaction was heated to 90 °C for 2 h, then cooled to RT, concentrated in vacuo. The residue was taken up in CH2C12, washed with brine, and extracted with CH2C12. The combined organic layers were dried over Na2S04. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2- tert-butyl 3-ethyl 8-(2-amino-6-((R)-l-(4-chloiO-3,-(methylsulfonyl)-[l,i,-biphenyl]-2-yl)-2,2J2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2J3-dicarboxylate as a white solid, Step 2: To a solution of (S)-2-tert-butyl 3-ethyi 8-(2-amino-6-((R)-l-(4-chloro-3'- (methylsulfonyl)-[l Jl,-biphenyl]-2-yl)-2,2)2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-2}3-dicarboxylate (500 mg, 0.65 mmol) in DMF (10 mL) was added tributyl(prop- l-enyl)stannane (258 mg, 0.78 mmol), Pd(t-Bu3P) 2 (33 mg, 0.065 mmol), and CsF (217 mg, 1.43 mmol). The reaction was heated to 130 °C in a sealed tube for 3 h, then cooled to RT. The reaction mixture was partitioned between water and CH2Cb, and extracted. The combined organic layers were washed with brine, dried over Na2S04} filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-tert- butyl 3-ethyl 8-(2-amino-6-((R)-2,2;2-trifluoro-l-(3'-(methy!sulfonyl)-4-(prop-l -en- 1 -yl)-[l ,Γ- biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2J8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Step 3: To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-aminO"6-((R)-2,252-trifluoiO-l-(3'- (methylsulfonyl)-4-(prop-l-en--l -yl)-[ljr-biphenyl]-2-yl)ethoxy)pyiimidin-4-yl)-2,8- diazaspiro[4.5]decane-2,3-dicarboxylate (200 mg, 0.26 mmol) in EtOH (10 mL) was added 10% Pd/C (200 mg) and the reaction mixture was stirred under 1 atm H2 for 12 h. The solids were filtered and the filtrate was concentrated to afford (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)- 2,2,2-ti'ifluoro-l -(3,-(methylsulfonylH
diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid that is used directly without further purification.
Step 4: To a solution of (S)-2 -tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'- (methylsulfonyl)-4-pi'opyl-[l,r-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO
[4.5]decane-2,3-dicarboxylate in CH2C12 (4 mL) was added TFA (2.0 mL) dropwise at 0 °C, The reaction mixture was stirred at RT for 2 h, then concentrated in vacuo. The pH was adjusted to 7-8 with saturated aqueous NaHC03 solution. The aqueous layer was extracted with CH2C12. The combined organic layers were washed with brine, dried over Na2S0 > filtered, and concentrated in vacuo. Purification by normal phase silica gel column (CH2Cl2 MeOH) provided the title compound as a white solid.
Ή NMR (400 MHz, MeOH-d4): δ ppm 8.41 (m, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.73-7.71 (m, 1H), 7.53 (s, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 6.61 (q, J - 6.7 Hz, 1H), 5.61 (s, 1H), 4.10 (t, J = 8.4 Hz, 1H), 3.72-3.63 (m, 2H), 3.55-3.46 (m, 2H), 3.26 (m, 1H), 3.21 (s, 3H), 3.16-3.13 (m, 1H), 2.66 (t, J = 7.6 Hz, 2H), 2.38-2.32 (m, 1H), 2.10- 2.05 (m, 2H), 1.65-1.60 (m, 3H). LCMS (MH+): 649. Example 50: (S)-8-(2-Amhio-6-((R)-2,2}2-trifluoro-l-(3,-(methylsuIfonyl)-4-((E)-prop-l-en- l-yl)-[l,l,-biphenyl]-2-yI)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000221_0001
The title compound was prepared as described for (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)- 2,2,2-triiluoi -l -(3'-(methylsulfonyl)-4-(prop-l-en-l-yl)-[l, -biphenyl]-2-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (Example 49) by omitting the olefin hydrogenation reaction of Step 3.
¾ NMR (400 MHz, CD3OD-d4): δ ppm 8.46-8.42 (m, III), 8.06-8.03 (m, ll-I), 7.82-7.71 (m, 2H), 7.64 (s, 1H)} 7.45 (dd, Jl = 8.2 Hz, J2 = 33.2 Hz, 1H), 7.25 (dd, Jl = 7.9 Hz, J2 = 23.9 Hz, 1H), 6.64-6.62 (m, 1H), 6.49-6.45 (m, 1H), 6.39-5.86 (m, 1H), 5.62 (d, J = 5.3 Hz, 1H), 4.12- 4.08 (m, 1H), 3.70-3.62 (m, 2H), 3.54-3.45 (m, 2H), 3.29-3.26 (m, 1H), 3.22-3.21 (m, 3H), 3.16- 3.13 (m, 1H), 2.37-2.31 (m, 1H), 2.10-2.05 (m, 1 H), 1.91 -1.87 (m, 3H), 1.62 (m, 4H). LCMS (MH+): 647. Example 51a: (S)-8-(6-((R)-l-([l,l':4',l"-terphenyI]-2,-yl)-2,2,2-tnfluoroethoxy)-2- aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000222_0001
Step /: To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-l-(2,5-dibromophenyl)-2j2,2- ti,ifluoiOethoxy)pyrimidin-4-yl)-2>8-diazaspiro[4.5]decane-2,3-dicarboxylate (660 mg, 0.95 mmol) in dioxane (12 mL) was added phenyl boronic acid (290 mg, 2.4 mmol), Pd2(dppf)Cl2 (70 mg, 0.095 mmol), and Na2CO3(6.0 mL, 2.0 M, aq). The reaction mixture was heated to 90 °C for 2 h, then cooled to RT, concentrated in vacuo, and extracted with CH2CI2. The combined organic layers were washed with brine, and dried over Na2SC>4. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-tert-butyl 3-ethyl 8-(6-((R)-l-([l,r:4',l"- teiphenyl]-2'-yl)-2,2J2-tiifluoiOethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-2,3- dicarboxylate as a white solid.
Step 2; To a solution of (S)-2-tert-butyl 3-ethyl 8-(6-((R)-l-([l,l':4',l"-terphenyl]-2'-yl)-2,2J2- trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspii [4.5]decane-2,3-dicarboxylate (550 mg, 0.75 mmol) in CH2CI2 (4 mL) was added TFA (2.0 mL) dropwise at 0 °C. The reaction mixture was stirred at RT for 2 h, and concentrated in vacuo. The pH was adjusted to 7-8 with a saturated aqueous NaHC03 solution. The aqueous layer was extracted with CH2CI2, The organic layer is wahed with brine, dried over Na2S04, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (CH2Cl2/MeOH) provided (S)-ethyl 8-(6-((R)-l-([l,l':4',l"- terphenyl]-2,-yl)-2,2,2-trifluoiOethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3- carboxylate as a white solid.
Step 3: Hydrolysis of (S)-ethyl 8-(6-((R)-l-([l,l':4',l"-terphenyl]-2,-yl)-2,2,2-trtfluoroethoxy)-2- aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provided the title compound as a white solid. Ή NMR (400 MHz, CD3OD-d4): 6 ppm 7.91 (s, 1H), 7.70 (dd, Jl= 6,08 Hz, J= 1.88 Hz, 1H),7.62 (m,2H), 7.56-7.44 (m,7H),7.39-7.35 (m, 2H), 6.72 (q, J = 6.52 Hz, 1H), 5.48(s, 1H), 4.18 (q, J = 6.96 Hz, 2H), 3.67 (m, 1H), 3.58 (m, 2H),3.41(m,2H), 2.98 (d, J = 10.96 Hz, 1H), 2.69 (d,J = l 1.24 Hz,lH), 2.12-2.06 (m,lH), 1.83-1.78 (m, 1H), 1.52 (m, 4H). LCMS (MH+): 604.5
Example 51b: (S)-8-(6-((R)-l-([l,l,:3,,l ,-terphenyl]-2,-yl)-2,2,2-trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8-di zaspiro[4.5]decane-3-carboxyIic acid
Figure imgf000223_0001
The title compound was prepared as described for (S)-8-(6-((R)-l-([l, :4',l"-terphenyl]-2,-yl)- 2,2,2-trifluoiOethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxyHc acid (Example 51 a) starting with (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-l-(2,6-dibromophenyl)- 2J2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-2J3-dicarboxylate (product of Step 4, example 63ao),
*H NMR (400 MHz, CD3OD-d4): δ ppm 1.32 (dd, J = 15.5, 7.9 Hz, 1H), 1.70 (dd, J = 7.9, 4.3 Hz, 5H), 2.12 (m, 1H), 2.49 (ddd, J = 12.3, 9.0, 2.6 Hz, 1H), 3.25 (dd, J = 1 1.9, 2.2 Hz, 1H), 3.60 (s, 9H), 4,48 (t, J = 8.6 Hz, 1H), 6.89 (q, J = 7.8 Hz, 1H), 7.21 (d, J = 7.6 Hz, 2H), 7,42 (m, 14H). LCMS (MH+): 604.
Example 52a: (S)-8-(2-Amino-6-((R)-l-(3,4-dimethyl-3"-(methylsulfonyI)-[l,r:3',l"- tcrphenyl]-4'-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]dccane-3- carboxylic acid
Figure imgf000224_0001
Step J: To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l-(5-chloiO-3'-(methylsulfonyl)- [l, -biphenyl]-2-yl)-2J2,2-trifluoroethoxy)pyrimidin-4-yl)-2}8-diazaspiro[4.5]decane-2,3- dicarboxylate (product of Step 1 , Example 34w) (273 mg, 0.34 mmol) in 1,4-dioxane (5 mL) was added (3,4-dimethylphenyl)boronic acid (77 mg, 0.51 mmol), KHCO3 (341 mg, 3.40 mmol), and Pd(PCy3)2 (34 mg, 0,051 mmol). The reaction was heated to 100 °C for 44 h. The reaction was charged with additional Pd(PCy3)2 (68 mg, 0.10 mmol) at t = 16 and 39 h. Then the reaction was cooled to RT and extracted with EtOAc, The combined organic layers were dried over N 2S0 ) filtered, and concentrated in vacuo. Purification on a 12 g Isco RediSep silica cartridge
(EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l-(3,4-dimethyl-3"- (methylsulfonylMU'^ 'MerphenylM'-yl)^^,^^
diazaspiiO[4.5]decane-2,3-dicarboxylate as an white solid.
Step 2 N-CBZ Deprotection was accomplished via Method B to provide (S)-ethyl 8-(2-amino- 6-((R)- 1 -(3 ,4-dimethyl-3"-(methylsulfonyl)-[l , 11 :3', 1 ,,-teiphenyl]-4,-yl)-2)2)2-trifiuoiOethoxy) pyrimidin"4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a white solid.
Step 3; Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-l-(3,4-dimethyl-3"-(methylsulfonyl)- [l,r:3', ,-terphenyl3-4,-yl)-2,2,2-trifiuoroethoxy) pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3- carboxylate using the Li OH general method provided the title compound as an off-white solid.
Using the generic scheme below, the following examples of Table 16a were prepared as described above for (S)-8-(2-amino-6-((R)-l-(3J4-dimethyl-3"-(methylsulfonyl)-[lill;3',l"- terphenyl]-4'-yl)-2,2,2-trifiuoroethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid (Example 52a).
Figure imgf000225_0001
T ble 16a.
Figure imgf000225_0002
Figure imgf000225_0003
Table 16b
NMR Data for Compounds of Table 16a
Figure imgf000225_0004
1 H) 2.28 (s, 3 H) 2.30 (s, 3 H) 2.32 - 2.40 (m, 1 H) 3.14 (d, J=l 1.76 Hz, 1 H) 3.22 (s, 3 H) 3.27 (d, J=l 1.76 Hz,l H) 3.40 - 3.77 (m, 4 H) 4.09 (dd, J=9.08, 7.27 Hz, 1 H) 5.62 (s, 1 H) 6.63 (q, J=6.64 Hz, 1 H) 7.18 (d, J=7.96 Hz, 1 H) 7.35 (dd, J=7.81, 1.81 Hz, 1 H) 7.40 (s, 1 H) 7.47 (d, J-1.85 Hz, 1 H) 7.63 -7.72 (m, 1 H) 7.72 - 7.77 (m, 1 H) 7.80 - 7.85 (m, 2 H) 8.07 (dt, J=6.97, 1.96 Hz, 1 H) 8.48 (br. s., 1 H)
52b Ή NMR (400 MHz, MeOH-d4): δ ppm 1 ,59 (t, J=5.54 Hz, 4 H) 1.92 (dd, J=13.13, 7.03 Hz, 1 H) 2.20 (dd, J=13.15, 9.10 Hz, 1 H) 2.81 - 3.17 (m, 2 H) 3.24 (s, 3 H) 3.38 - 3.74 (m, 4 H) 3.84 (dd, J=8.96, 7.05 Hz, 1 H) 5.64 (s, 1 H) 6.67 (q, J=6.64 Hz, 1 H) 7.55 (dd, J=8,35, 4.34 Hz, 1 H) 7.67 (d, J=1.61 Hz, 1 H) 7.78 - 7.92 (m, 4 H) 8.04 - 8.15 (m, 3 H) 8.21 (s, 1 H) 8.41 (dd, J=8.40, 1.56 Hz, 1 H) 8.54 (br. s., 1 H) 8.84 (dd, J=4.32, 1.68 Hz, 1 H)
Example 53: (S)-8-(2-Amino-6-((R)-2,2,2-trifluoro-l-(3'-(methylsulfonyl)-5-((E)-prop-l-en- l-yl)-[l,l'-biphenyl]-2-yI)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.S]decane-3-carboxylic acid
Figure imgf000226_0001
Step h To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-l-(2-bromo-4-chlorophenyi)- 2J2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-2,3-dicarboxylate (600 mg, 0.89 mmol) in dioxane (12 mL) was added (3-(methylsulfonyl)phenyl)boronic acid (275 mg, 1.3 mmol), Pd2(dppf}Cl2 (65 mg, 0.095 mmol), and Na2C03 (6.0 mL, 2.0 M, aq). The reaction was heated to 90 °C for 2 h, then cooled to RT, and concentrated in vacuo. The residue was taken up in CH2CI2, wahed with brine, and dried over Na2S04. Purification by normal phase silica gel column (EtO Ac/heptane) provides (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-l-(5-chloro-3'- (methylsulfonyl)-[ljr-biphenyl]-2-yl)-2,2,2-trifiuoiOethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Step 2: To a solution (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-l-(5-chloiO-3'-(methylsulfonyl)- n} -biphenyl]-2-yl)-2}2,2-tiifluoroethoxy)pyrimidin-4-yl)-2J8-diazaspii [4.5]decane-2,3- dicarboxylate (500 mg, 0.65 mmol) in DMF (10 mL) was added tributyl(prop-l-enyl)stannane (258 mg, 0.78 mmol), Pd(t-Bu3P) 2 (33 mg, 0.065 mmol), and CsF (217 mg, 1.43 mmol). The reaction was heated to 130 °C in a sealed tube for 3 h, then cooled to RT, and partitioned between between water and CH2C12. The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo, Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoi -l-(3'- (methyisulfonyl)-5-((E)-piOp-l -en-1 -yl)-[l , 1 '-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Step 3: To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoi -l-(3'- (methyisulfonyl)-5-((E)-prop- 1 -en- 1 -yl)-[l ,r-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-2,3-dicarboxylate in CH2CI2 (4 mL) was added TFA (2.0 mL) dropwise at 0 °C. The reaction mixture was stirred at RT for 2 h, then concentrated in vacuo. The pH was adjusted to 7-8 with a saturated aqueous NaHCOs solution. The aqueous layer was extracted with CH2Cl2, washed with brine, dried over Na2S0 , filtered, and concentrated in vacuo. Purification by normal phase silica gel column (CFbCh/MeOH) provided (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-l-(3,-(methylsulfonyl)-5-((E)-prop-l -en-l-yl)-[l;r-biphenyl]-2-yl)ethoxy)pyrimidi yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a white solid.
Step 4 Hydrolysis of (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l -(3'-(methylsulfonyl)-5-((E)-prop-l - en- 1 -yl)-[l , 1 '-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2}8-diazaspiro[4.5]decane-3-carboxylic acid using the LiOH general method provided the title compound as an off-white solid.
Ή NMR (400 MHz, CD3OD-d4): δ ppm 8.40 (s, 1 H), 8.02 (d, 1 H;J=7.4 Hz), 7.50 (m, 3 H), 7.40 (m, 1 H), 7.20 (m, 1 H), 6.58 (m, 1 H), 5.58 (m, 1 H), 4.09 (m, 1 H), 3.55 (m, 2 H), 3.48 (m, 2 H), 3.21 (m, 4H), 3.10 (m, 1 H), 2.59 (m, 2 H), 2.29 (m, 1 H),1.95 (m, 1 H), 1.86 (m, 3 H), 1.30 (m, 4 H). LCMS ( H+): 646.
Example 54a: (S)-8-(2-Amino-6-((R)-2,2,2-tnfluoiO-l-(3,-(methylsulfonyl)-5-propyl-[l,l'- biphenyI]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000228_0001
Step 1: To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-ammo-6-((R 2,2,2-trifluoiO-l-(3'- (methylsulfonyl)-5-((E)-prop-l -en- 1 -yi)-[l j -biphenyl]-2-yl)ethoxy)pyi*imidin-4-yl)-2,8- diazaspii [4,5]decane-2,3-dicarboxylate (product from Step 2, Example 53) (200 mg, 0.26 mmol) in EtOH (10 n L) is added 10% Pd/C (200 mg), and the reaction mixture was stirred under 1 atm H2 for 12 h. The solids were filtered and the filtrate was concentrated in vacuo to provide (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifiuoiO-l -(3 -(methylsuifonyl)-5- propyl-[l ;r-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4,5]decane-2,3-dicarboxylate as a white solid that is used directly without further purification.
Step 2: To a solution of (S)-2-tert-butyI 3-ethyl 8-(2-amino-6-((R)-2,2,2-irifluoiO-l-(3'- (methylsulfonyl)-5-propyl-[l, -biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5] decane-2,3-dicarboxylate in CH2C12 (4 mL) was added TFA (2.0 mL) dropwise at 0 °C. The reaction mixture was stirred at RT for 2 h, then concentrated in vacuo. The pH was adjusted to 7-8 with saturated aqueous NaHC03 solution. The aqueous layer was extracted with CH2C12, washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (CH2CI2/MeOH) provided (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoi -l-(3'-(methylsulfonyl)-5-piOpyl-[l,r-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiio[4.5]decane-3-carboxylate as a white solid.
Step 3; Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-2>2,2-trifluoro- l-(3'-(methylsulfonyl)-5- propyl-[l ,l '-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2}8-diazaspiiO[4.5]decane-3-carboxylate using the LiOH general method provides the title compound as an off-white solid.
Ή NMR (400 MHz, CD3OD-d4): δ ppm 8.40 (s, 1 H), 8.02 (d, 1 H,J=7.8 Hz), 7,60 (m, 3 H), 7.29 (m, 1 H), 7.08 (s, 1 H), 6.58 (ra, 1 H), 5.56 (s, 1 H), 4.00 (m, 1 H), 3.55 (m, 2 H), 3.48 (m, H), 3.31 (m, 4H), 3.30 (m, 1 H), 2.59 (m, 2 H), 2.29 (m, 1 H),1.95 (m, 1 H), 1.54 (m, 6 H), 0.95 (m, 3 H). LCMS (MH+): 649.
Example 54b: (S)-8-(2-amino-6-((R)-2,2,2 rifluoro-l-(4-isopiOpoxy-fl,r:3,, ,-terp enyI]- 4'-yl)ethoxy)pyrimidin-4- l)-2)8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000229_0001
Step h To a solution of (S)-ethyl 8-(2-amino-6"((R)-l-(5-bi mo-[l,r-biphenyl]-2-yl)-2J2)2- trifluoi'oethoxy)pynmidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate (350 mg, 0.56 mmol) in CH2C12 (20 mL) was added B0C2O (436 mg, 2.0 mmol) and Et3N (306 mg, 3.03 mmol) at 0 °C. The reaction mixture was stirred at RT for 3 h, then concentrated in vacuo and purified on normal phase silica gel (ethyl acetate/hexanes) to afford (S)-2-tert-butyl 3-ethyl 8-(2-amino-6- ((R)-l-(5-biOmo-[l,r-biphenyl]-2-yl)-2,2s2-trifluoroethoxy)pynmidin-4-yl)-2,8- diazaspiro[4.5]decane-2,3-dicarboxylate as a yellow solid. Step 2 A solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-l-(5-bromo-[lJl,-biphenyl]-2- yl)-2,2,2-trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-2,3-dicarboxylate (150 mg, 0.2 mmol), 4-isopropoxyphenyl boronic acid (44 mg, 0.25 mmol) and Pd(dppf)Cl2 (15 mg, 0.02 mmol) in dioxane (3.0 mL) / aqueous Na2C03 solution (3.0 mL, 2.0 M, aq.) was stirred at 90 °C for 2 h. The aqueous layer was extracted with CH2CI2, washed with brine, dried over Na2S0 } filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/ Hex = 10 to 50 %) to (S)-2~tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-l -(4-isopropoxy- [l}r:3\l''-teiphenyl]-4'-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid. Step 3: To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro- 1-(4- isopropoxy- [ 1 , 1 ' : 3 ', 1 "-terphenyl]-4'-yl)ethoxy)pyrimidin-4-yl)-2, -diazaspiro [4.5]decane-2,3 - dicarboxylate (130mg, 0.164 mmol) in CH2CI2 (4 mL) was added TFA (1 mL), and the reaction mixture was stirred at 25 °C for 12 h. The mixture was concentrated, and neutralized to pH 7-8 with saturated aqueous NaHC03. The aqueous layer was extracted with CH2C12} washed with brine, dried over Na2S04) filtered, and concentrated in vacuo to provide (S)-ethyl 8-(2-amino-6- ((R)-2,2J2-trifluoi -l -(4-isopiOpoxy-[l}l,:3,,r,-terphenyl]-4,-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate as a light yellow solid that is used without further purification.
Step 4: Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-2)2)2-trifluoiO-l-(4-isopropoxy-[lJl':3'}l"- terphenyl]-4'-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate using the LiOH general method provided the title compound as an off-white solid.
Ή NMR (400 MHz, MeOH-d4): δ ppm 1.31 (d, J = 6.0 Hz, 6H), 1.58 (m, 4H), 2.04 (dd, J = 13.4, 7.2 Hz, 1H)5 2.32 (dd, J = 13.4, 9.2 Hz, 1H), 3.11 (d, J = 1 1.7 Hz, 1H), 3.24 (d, J = 11.7 Hz, 1H), 3.45 (ddd, J = 21.2, 10.1 , 6.4 Hz, 2H)} 3.60 (td, J = 12.4, 11.2, 6.0 Hz, 2H), 4.08 (dd, J - 9.1, 7.1 Hz, 1H), 4.62 (p, J = 6.1 Hz, 1H), 6.67 (q, J = 6.8 Hz, 1H), 6.95 (m, 2H), 7.54 (m, 9H), 7.72 (d, J = 8.3 Hz, 1H), LCMS (MH+): 663.
Example 54c: (S)-8-(2-amino-6-((R)-2J2,2-trifluoro-l-(4- lΌ oxy-[l,l':3',l',-ter hen l]-4,- yl)ethoxy)pyrimidin- -yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000230_0001
The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro- (4-isopiOpoxy-[l, :3',l"-terphenyl]-4'-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3- carboxylic acid (Example 54b) by substituting 4-propoxyphenyl boronic acid for 4- isopropoxyphenyl boronic acid in Step 2. Ή NMR (400 MHz, MeOH-d4): δ ppm 1.04 (t, J = 7.4 Hz, 3H), 1.57 (m, 4H), 1.80 (h, J = 6.7 Hz, 2H), 1.99 (dd, J = 13.3, 7.3 Hz, 1 H), 2.27 (dd, J = 13.3, 9.1 Hz, 1H), 3.02 (d, J - 1 1.6 Hz, l H), 3.18 (d, J = 1 1.5 Hz, 1H), 3.30 (d, J = 3.2 Hz, 1H), 3.45 (q, J = 15.9, 1 1.4 Hz, 2Ή), 3.60 (s, 2H), 3.97 (dt, J = 13.1, 7.3 Hz, 3H), 4.88 (m, 1H), 5.47 (s, 1H), 6.66 (q, J = 6.9 Hz, 1H), 6.97 (d, J = 8.3 Hz, 2H), 7.54 (m, 9H), 7.72 (m, 1H). LCMS (MH+): 662.
Example 54d: (S)-8-(2-amino-6-((R)-2J2,2-trifluoro-l-(5-(methylsulfonyl)-[l,l'-biphenyl]-2- yl)ethoxy)pyrimidin-4-yI)-2 -diazaspii'o[4.5]decane-3-carboxylic acid
Figure imgf000231_0001
Step 1 : To a mixture of 2-chloro-4-(methylsulfonyl)benzoic acid (5 g, 21.3 mmol) in anhydrous methanol (100 mL) was added concentrated sulfuric acid (0,5 mL). The resulting solution was stirred for 18 h at reflux. Upon cooling, the mixture was concentrated under reduced pressure, dissolved in CH2C12 and washed with NaHC03 solution and brine. The organic phase was dried over sodium sulfate and concentrated to afford methyl 2-chloro-4-(methylsulfonyl)benzoate as a white solid.
Step 2: To a mixture of methyl 2-chloro-4-(methylsulfonyl)benzoate (2.2 g, 8.9 mmol),
PhB(OH)2 (1.31 g, 10.8 mmol), DME (12 mL), and 2M Na2C03 (6 mL) was added Pd(PPh3 t (515 mg). The mixture was heated for 20 min at 160 °C in a microwave reactor, and then extracted with EtOAc, dried over sodium sulfate and concentrated in vacuo. Purification on normal phase silica gel (hexane/EtOAc) provided methyl 5-(methylsulfonyl)-[l,r-biphenyl]-2- carboxylate as a white solid. Step 3: To a solution of CaCl2 (1.52 g, 13.78 mmol) in EtOH (50 mL) at RT was added methyl 5- (methylsulfonyl)-[l,l '-biphenyl]-2-carboxylate (2 g, 6.9 mmol) in THF (50 mL) followed by the addition of NaBH4 (1 ,0 g, 27.6 mmol). The reaction was stirred at RT for 24 h, then concentrated in vacuo and extracted with ethyl acetate, 5% HC1, and brine. Purification on normal phase silica gel provided (5-(methylsulfonyl)-[l,l'-biphenyl]-2-yl)methanol as a white solid.
Step 4: To a solution of (5-(methyisulfonyl)-[l, -biphenyl]-2-yl)methanol (1 g, 3.8 mmol) in CH2Cb (50 mL) was added Dess-Martin periodinane (2.4 g, 5.71mmol). The reaction was stirred for 2 h at RT, then concentrated in vacuo and purified directly on normal phase silica gei to provide 5-(methylsulfonyl)-[l,r-biphenyl]-2-carbaldehyde as a white solid.
Step 5: To a solution of 5-(methylsulfonyl)-[l,r-biphenyl]-2-carbaldehyde (1 g, 3.8 mmol) was added TMS-CF3 (1.0 g, 7.7 mmol) in THF (10 mL). The reaction was cooled to 0 °C to and TBAF (0.57 mL, 0.57 mmol) was added dropwise. The reaction mixture was stirred for 2 h, then 3 N HC1 (2 mL) was added to the mixture and the reaction mixture was stirred for an additional 30 min. The mixture was extracted with ethyl acetate, washed with brine, dried over Na2S0 , filtered, and concentrated in vacuo. Purification on normal phase silica gel provided 2,2,2- trifluoro-l-(5-(methylsulfonyl)-[l, -biphenyl]-2-yl)ethanol as a white solid.
Step 6: To a mixture of 2,2,2-trifluoi -l-(5-(methylsulfonyl)-[l,r-biphenyl]-2-yl)ethanol (720 mg, 2.2 mmol) ) in CH2CI2 (50 mL) was added Dess-Martin periodinane (1.1 g, 2.6mmol). The reaction was stirred for 2 h at RT, then concentrated in vacuo and purified directly on normal phase silica gel to provide 2,2,2-trifiuoi -l-(5-(methy]suifonyl)-[l, -biphenyl]-2-yl)ethanone as a white solid. Step 7: Chiral reduction of 2,2,2-tnfluoiO-l-(5-(methylsutfonyl)-[l,l'-biphenyl]-2-yl)ethanone using the Iridium complex-catalyzed hydrogenation as described for Intermediate 1 , (R)-l-(4- bromo-2-(3-methyl- 1 H-pyrazol- 1 -yl)phenyl)-2,2,2-trifluoiOethanol, provided (R)-2,2,2-trifluoro- l -(5-(methylsulfonyl)-[l, -biphenyl]-2-yl)ethanol as a white solid. Steps 8-11: The title compound was prepared as described for (S)-8-(2-amino-6-((R)-l-(4- chloiO-2-(3-methyl-lH-pyrazol-l -yl)phenyl)-2,2,2-trifluoi ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid (Example lOd), Steps 1-4.
Ή NMR (400 MHz, MeOH-d4): δ ppm 1.63 (q, J = 5.7, 4.9 Hz, 4H), 2.10 (m, 1H), 2.36 (dd, J = 13.5, 9.2 Hz, 1 H), 3,23 (d, J = 31.0 Hz, 5H), 3.50 (dddd, J = 18.0, 13.4, 9.5, 5, 1 Hz, 2H), 3.66 (ddt, J = 15.9, 10.6, 4.6 Hz, 2H), 4.16 (dd, J = 9.2, 7.2 Hz, 1H), 6.78 (q, J - 6.7 Hz, 1H), 7.57 (m, 5H), 7.86 (d, J = 1.9 Hz, 1H), 8.01 (m, 2H), 8.17 (s, 1H). LCMS (MH+): 607.
Example 54e: (S)-8-(2-amino-6-((R)-2,2,2-irifluoi -l-(3-fluoro-4-propoxy-[l,l,:3',l"- terphenyl]-4,-yl)eth boxylic acid
Figure imgf000233_0001
The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l - (4-isopropoxy-[l, :3', ,-terphenyl]-4'-yl)ethoxy)pyrimidin-4-yl)-2;8-diazaspiro[4.5]decane-3- carboxylic acid (Example 54b) by replacing the 4-isopropoxyphenyl boronic acid in Step 2 with (3-fluoro-4-propoxyphenyl)boronic acid (CAS# 192376-68-4).
Ή NMR (400 MHz, MeOH-d4): δ ppm 0.86 (m, 1H), 1.05 (t, J = 7.4 Hz, 3H), 1.26 (s, 1H), 1.59 (s, 4H), 1.83 (h, J = 7.1 Hz, 2H), 2.06 (dd, J = 13.4, 7.2 Hz, 1H), 2.33 (m, 1H), 3.10 (d, J = 11.9 Hz, 1H), 3.23 (d, J = 12,0 Hz, 1H), 3.43 (s, 2H), 3.60 (s, 2H), 4.02 (t, J = 6.5 Hz, 2H), 4.12 (s, 1H), 6.62 (d, J = 6.8 Hz, 1H), 7.09 (t, J = 8.7 Hz, 1H), 7.34 (s, 1H), 7.43 (m, 4H), 7.50 (s, 3H), 7.60 (m, 1H), 7.76 (m, 2H). LCMS (MH+): 681.
Example 54f: (S)-8-(2-amino-6-((R)-l-(3,4-dimethyl-[l,l,;3',l"-terpheny]]-4'-yl)-2,2)2- trifIuoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000234_0001
The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-2}2,2-trifluoro-l- (4-isopiOpoxy-[l,r:3'; '-terphenyl]-4'-yl)ethoxy)pyi'imidin-4-yl)-2,8-diazaspiro[4,5]decane-3- carboxylic acid (Example 54b) by replacing the 4-isopropoxyphenyl boronic acid in Step 2 with 3,4-dimethylphenyl boronic acid.
'H MR (400 MHz, MeOH-d4): δ ppm 1.62 (s, 4H), 2.06 (dd, J = 13.5, 7.6 Hz, 1H), 2.29 (d, J = 9.7 Hz, 5H), 2.37 (m, 1 H), 3.17 (d, J = 1 1.8 Hz, 1H), 3.26 (d, J = 1 1.7 Hz, 1H), 3.63 (d, J = 14.2 Hz, 2H), 4.27 (t, J = 8.3 Hz, 1H), 6.66 (q, J = 6.8 Hz, 1H), 7.18 (d, J = 7.9 Hz, 1H), 7.36 (m, 2H), 7.49 (m, 5H), 7.64 (dd, J = 8.2, 2.0 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H). LCMS (MH+): 633.
Example 54g: (S)-8-(6-((R)-l-([l,r:3',lM-terphenyl]-4'-yl)-2,2,2-trifluoroethoxy)-2- aminopyrimidin-4-yl)-2,8-diazaspiro[4,5]decane-3-carboxylic acid
Figure imgf000234_0002
The title compound was prepared as described above for (S)-8-(2-ainino-6-((R)-252,2-trifluoro-l- (4-isopiOpoxy-[l,1^3', '-terphenyi]-4'-yl)etl oxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3- carboxylic acid (Example 54b) by substituting phenyl boronic acid for 4-isopropoxyphenyl boronic acid in Step 2. Ή NMR (400 MHz, MeOH-d4): 8 ppm 1.62 (s, 4H), 2.06 (dd, J = 13.5, 7.7 Hz, 1H), 2.38 (dd, J = 13.5, 9.1 Hz, 1H), 3.16 (d, J = 1 1.8 Hz, iH), 3.26 (d, J = 1 1.8 Hz, 1H), 3.47 (s, 2H), 3.62 (s, 2H)} 4.26 (t, J = 8.4 Hz, 1H), 6.68 (q, J = 6.9 Hz, 1H), 7.35 (m, 1H), 7.47 (m, 4H), 7.53 (s, 3H), 7.66 (m, 3H), 7.77 (d, J - 8.2 Hz, 1H). LCMS (MH+): 604.
Example 54h: (R)-8-(2-amino-6-((R)-l-(S-chloro-(l,l'-biphenyl]-2-yl)-2,2,2- trifluorocthoxy)pyr nidin- -yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid H
Figure imgf000235_0001
The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-l-(5-chioro- [l, -biphenyl]-2-yl)-2,2J2-ti fluoiOethoxy)pyi1midin-4-yl)-2,8-diazaspii [4.5]decane-3- carboxylic acid (Example 34c) by using (R)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l-(2-bromo-4- chlorophenyl)-2,2}2-trifluoi ethoxy)pyriinidin-4-yl)-2!8-diazaspiiO[4.5]decane-2,3- dicarboxylate.
*H NMR (400 MHz, MeOH-d4): δ ppm 1 .59 (d, J = 5.5 Hz, 4H), 2.03 (dd, J = 13.4, 7.1 Hz, 1H), 2.31 (dd, J = 13.4, 9.2 Hz, 1H), 3.09 (d, J - 11.8 Hz, 1H), 3.23 (d, J = 1 1.6 Hz, 1H), 3.46 (dt, J = 15.3, 8.2 Hz, 2H), 3.62 (s, 2H), 4.06 (dd, J = 9.1, 7.1 Hz, 1H), 5.49 (s, 1H), 6.64 (q, J = 6.9 Hz, 1H), 7.28 (d, J = 2.2 Hz, 1H), 7.46 (m, 5H), 7.53 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H). LCMS (MH+): 562.
Example 541: (R)-8-(2-amino-6-((S)-l-(5-chloro-[l,l'-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin- -yl)-2,8-diazaspiro[4.S]decane-3-carboxylic acid
Figure imgf000235_0002
e compound was prepared as described above for (S)-8-(2-amino-6-((R)-l-(4-chloro-2-(3- methyl- 1 H-pyrazol- 1 -yl)phenyl)-2)2,2-tnfluoiOethoxy)pyrimidin-4-yl)-2;8- diazaspiiO[4.5]decane-3-carboxylic acid (Example 34c) by using (R)-2-benzyl 3-ethyl 8-(2- amhio-6-((S)-l-(2-biOmo-4-chloi phenyl)-2J2,2-ti'ifluoi ethoxy)pyrimidin-4-yl)-2J8- diazaspiro[4.5]decane-2,3-dicai'boxylate,
Ή NMR (400 MHz, MeOH-d4): δ ppm 7.70 (d, J = 8.5 Hz, 1H), 7.59 - 7.44 (m, 4H), 7.47 - 7.40 (m, 2H), 7.32 (d, J = 2.2 Hz, 1H), 6.61 (q, J = 6.5 Hz, 1H), 4.51 (t, J = 8.7 Hz, 1H), 3.72 - 3.59 (m, 1H), 3.56 (s, 1H), 3.28 (s, 1H), 2.49 (dd, J = 13.6, 8.9 Hz, 1H), 2.10 (dd, J - 13.6, 8.4 Hz, 1H), 1.71 (dt, J = 16.0, 6.6 Hz, 4H), 1.28 (s, 0H).LCMS (MH+): 562.
Example 54j: (S)-8-(2-amino-6-((S)-l-(5-chloro-[l,l'-biphenyl]-2-yl)-2,2,2- tnfluoiOethoxy)pyrimidin- -yl)-2,8-diazaspiro[4.5]decane-3-carboxyIic acid
Figure imgf000236_0001
The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-l-(4-chloro-2-(3- methyl-lH-pyrazol-l-yl)phenyl)-2,2,2-tnfluoi ethoxy)pyiimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid (Example 34c) by using (S)-2-benzyl 3-ethyl 8-(2- amino-6-((S)-l-(2-biOmo-4-chloiOphenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4.5]decane-2,3 -dicarboxylate. Ή NMR (400 MHz, MeOH-d4): δ ppm 7.70 (d, J = 8.5 Hz, 1H), 7.61 - 7.42 (m, 6H), 7.32 (d, J = 2.3 Hz, 1H), 6.66 (q, J = 6.7 Hz, 1H), 4.25 (dd, J - 9.0, 7.6 Hz, 1H), 3.72 - 3.60 (m, 1H), 3.29 (d, J = 1 1.7 Hz, 1H), 3.18 (d, J = 1 1.8 Hz, 1H), 2.40 (dd, J = 13.5, 9.2 Hz, ΪΗ), 2.09 (dd, J = 13.5, 7.6 Hz, 1H), 1.64 (s, 2H).LCMS (MH+): 562. Example 54k: (S)-8-(2-amino-6-((S)-l-(3 4,-dimethyl-3-(3-methyl-lH-pyrazol-l-yl)-[l,l'- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4,5]decane-3- carboxylic acid
Figure imgf000237_0001
The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-l -(3',4'- dimethyl-3-(3-methyl-lH-pyrazol-l-yI)-[l J'-biphenyl] -yl)-2,2,2-trifluoiOethoxy)pyiimidin-4- yl)-2,8-diazaspiro [4.5]decane-3-carboxylic acid (Example lm) by using (S)-2-benzyl 3-ethyl 8- (2~amino-6-((S 1 -(4-chloro-2-(3 -methyl- 1 H-pyrazol- 1 -yl)phenyl)-2J2,2- trifluoro ethoxy)pyrimidin- 4 -y 1) -2 , 8 -diazaspi ro [4.5] decane-2,3 -dicarboxyl ate .
Ή N R (400 MHz, MeOH-d4): 8 ppm 1.58 (s, 6H), 2.04 (dd, J = 13.4, 7.2 Hz, 1H), 2.30 (d, J = 1 1.1 Hz, 9H), 2.40 (s, 3H), 3.10 (d, J = 1 1.8 Hz, 1H), 3.23 (d, J = 11.7 Hz, 1H), 3.48 (s, 2H), 3.66 (d, J = 15.7 Hz, 3H), 4.08 (t, J = 8.2 Hz, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.77 (q, J = 6.5 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 8.0 Hz, IH), 7.44 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 1.8 Hz, 1H), 7.73 (m, 2H)} 7.97 (d, J = 2.4 Hz, 1H). LCMS (MH+): 635.
Example 541: (R)-8-(2- mino-6-((S)-l-(3 4'-dimethyl-3-(3-methyl-lH- razoI-l- l)-[l>l,- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
Figure imgf000237_0002
The title compound was prepared as described above for (R)-8-(2-amino-6~((R)-l-(3',4'- dimethyl-3-(3-methyl-lH-pyrazol-l -yl)-[l) -biphenyl]-4-yl)-2J2,2-trifluoroethoxy)pyrimidn^ yl)-2,8-diazaspiro [4.5]decane-3-carboxylic acid (Example lm) by using (R)-2-benzyl 3-ethyl 8- (2~amino-6-((S)- 1 -(4-chloro-2-(3 -methyl- 1 H-pyrazol- 1 -yl)pheny l)-2,2,2- trifluoi ethoxy)pyiimidin-4-yl)-2,8-diazaspiiO[4.5]decane-2,3-dicarboxylate.
!H NMR (400 MHz, MeOH-d4): δ ppm 7.97 (d, J = 2.3 Hz, OH), 7.79 - 7.69 (m, OH), 7.61 (d} J = 1.6 Hz, OH), 7.45 (s5 OH), 7.42 - 7.35 (m, OH), 7.21 (d, J = 7.9 Hz, OH), 6,77 (q, J = 6.5 Hz, OH), 6.41 (d, J = 2.3 Hz, OH), 4.10 (t, J = 8.2 Hz, OH), 3.68 (dd, J = 13.9, 6.3 Hz, OH), 3.58 - 3.43 (m, OH), 3.24 (d, J = 11.7 Hz, OH), 3.1 1 (d, J = 11 ,8 Hz, OH), 2.42 - 2.27 (m, 1H), 2.05 (dd, J = 13,5, 7,2 Hz, OH), 1.59 (d, J = 1 1.4 Hz, OH), 1.59 (s, OH).. LCMS (MH+): 635.
Example 54m: (R)-8-(2-amίno-6-((R)-l-(3^4'-dimethy!-3-(3-meth l-lH- razoI-l-yl)-[l,l,- bipheiiyI]-4-yl)-2,2,2-trifluoroethoxy)pyrimidiii-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid
Figure imgf000238_0001
The title compound was prepared as described above for (R)-2-benzyl 3-ethyl 8-(2-amino-6- ((R)-l-(4-chloiO-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoi ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro [4.5]decane-2,3-dicarboxylate (Example lm) by using (R)-2-benzyl 3-ethyl 8-(2- amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoiOethoxy)pyi'imidin- 4-yl) -2 , 8 -diazaspi io [4.5] dec ane-2 ,3 - dicarboxylate .
Ή NMR (400 MHz, MeOH-d4): δ ppm 7,97 (d, J = 2.4 Hz, 1H), 7,79 - 7.68 (m, 2H), 7.60 (d, J = 1.7 Hz, 1H), 7.44 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 6.76 (q, J = 6.7 Hz, 1H), 6,41 (d, J = 2.3 Hz, 1H), 5.75 (s, 1H), 3.98 (t, J = 8.1 Hz, 1H), 3,64 (d, J = 15.5 Hz, 3H), 3.47 (s, 2H), 3,33 - 3.27 (m, 6H), 3,17 (d, J = 11.6 Hz, 1 H), 3.01 (d, J = 11.6 Hz, 1H), 2.39 (s, 3H), 2,34 - 2.18 (m, 8H), 1.99 (dd, J = 13.4, 7.1 Hz, 1H), 1.56 (s, 5H), LCMS (MH+): 635. Example 55an: (Si-S-i - mino-e-ii^-l^^-trifluoro-l-tS'-methoxy-Il.r-bi hen ll- - yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000239_0001
Step 1 : To a solution of (R)-l-(4-bi mophenyl)-2J2,2-trifluoi ethanol (150 mg, 0.60 mmol) in dioxane (10 mL) was added 4,6-dichloropyrimidin-2-amine (120 mg g, 0.71 mmol) and Cs2C03 (290 mg, 0.88 mmol), and the reaction mixture was heated to 80 °C for 30 h. Then the reaction was cooled to RT, EtO Ac was added and the organic layer was washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. Purification by normal phase silica gei column (EtO Ac/heptane) provided (R)-4-(l-(4-bi mophenyl)-2,2,2-trifluoroethoxy)-6-chloropyrimidin- 2-amine as a colorless oil.
Step 2: To a solution of (R)-4-(l-(4-bromophenyl)-2,2,2-trifluoroethoxy)-6-chloiOpyrimidin-2- amine (19 mg, 0,50 mmol ) in dioxane (25 ml) was added (S)-2-benzyl 3-ethyl 2,8- diazaspiro[4.5]decane-2,3-dicarboxylate (175 mg, 0,50 mmol) and sodium bicarbonate (210 mg, 0.25 mmol), and the reaction mixture was heated to 100 °C for 48 h. Then the reaction mixture was cooled to RT, and extracted with EtO Ac. The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtO Ac/heptane) provided (S)-2-benzyl 3~ethyl 8-(2-amino-6-((R)-l-(4- biOmophenyl)-2,2,2-trifluoroethoxy)-pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3- dicarboxylate as white solid.
Step 3: To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l-(4-bromophenyl)-2,2,2- trifluoiOethoxy)-pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-2;3-dicarboxylate (190 mg, 0.27 mmol) was added NaOH (100 mg, 0.26 mmol) in 15 mL THF7EtOH/H20 (2/1/2.5), and the reaction was stirred for 12 h at RT. Then, the reaction mixture was concentrated in vacuo to remove most of the organic solvents, and the pH was adjusted to 6 with 1 N HQ. EtOAc was added, and the organic layer was washed with brine, dried over a2S04) filtered, and
concentrated in vacuo to provide (S)-8-(2-amino-6-((R)-l-(4-biOmophenyl)-2,2,2- trifluoroethoxy) pyrimidin-4-yl)-2-(benzyloxycarbonyl)-2,8-diazaspiiO[4,5]decane-3-carboxylic acid as a white solid which was used without further purification.
Step 4: To a solution of (S)-8-(2-amino-6-((R)-l-(4-bromophenyl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (80 mg, 0.12mmol) in dioxane (1 mL)/Na2CO3(1.0 mL, 2 M, aq) were added (3~methoxyphenyl)boronic acid (22 mg, 0.14 mmol) and Pd(dppf)2 (8 mg, 0.01 mmol). The reaction flask was degassed and refilled with argon via balloon 3 times, and the reaction mixture was refluxed for 4 h. Then the reaction was cooled to RT, concentrated in vacuo, and extracted with EtOAc. The combined organic layers were are washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. Purification by reverse phase silica gel column (H20/NH40H/MeOH) provided (S)-8-(2- amino-6-((S)-2,2,2-trifluoro-l-(3'-methoxy-[l, -biphenyl]-4-yl)ethoxy)pyrimidin-4-yI)-2- ((benzyIoxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as a white solid.
Step 5: N-CBZ Deprotection was accomplished via Method A to provide the title compound as an off-white solid isolated as the zwitterionic form.
Using the generic scheme below, the following examples of Table 17a were prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoiO-l-(3'-methoxy-[l ,l'-biphenyl]-4- yi)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid (Example 55an) using the appropriate boronic acid or boronate In some cases, the Cy coupling reaction was performed prior to ethyl ester and N-CBz removal (see alternative Steps 3a and 4a) as noted in the scheme. In the cases of example 55al and 55am, racemic l -(4-biOmophenyl)-2,2,2-trifiuoroethanol was used as opposed to (R)-l -(4-bi mophenyl)-2,2,2-trifluoroethanol for all other examples.
Figure imgf000241_0001
Figure imgf000241_0002
240 Ex. Cy CAS Name LCMS (MH+) No.
55a (S)-8-(6-((R)-l-([l)i'-biphenyI]-4-yl)-2,2}2- 529
trifluoroethoxy)-2-aminopyrimidin-4-yl)-2;8- diazaspiro [4 , 5 ]decane-3 -c arb oxy lie acid
55b (S)-8-(2-amino-6-((R)-2,2,2-trifluoi -l-(4-(l- 583
JA methyl - 1 H- i ndazol-5- yl)phenyl)ethoxy)pyiimidin-4-yl)-2,8- diazaspiiO[4.5]decane-3-carboxylic acid
55c (S)-8-(2-amino-6-((R)-2>2,2-trifluoro-l-(4-(l - 583
-' methyl- 1 H-benzo [d] i m idazol-5 - yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspho[4.5]decane-3-carboxylic acid
55d (S)-8-(6-((R)-l-(4-(lH-benzo[d]imidazol-5- 569
yl)phenyl)-2s2,2-trifluoroethoxy)-2- aminopy r i m idin-4-yl)-2 , 8 -diazaspir o [4.5 ]decane-
Figure imgf000242_0001
3-carboxyIic acid
55e (S)-8-(2-ammo-6-((R)-2,2,2-trif]uoiO-l-(3'~ 577
"A fluoro-4'-methoxy- [ 1 , -biplieny 1] -4 - yl)et oxy)py rimidin-4 -y 1) -2 , 8 - diazaspiro[4.5]decane-3-carboxylic acid
55f (S)-8-(2-amino-6-((R)-l-(4-(benzo[djisothiazol- 586
6-y l)phenyl) -2 ,2 ,2-tr i fluoroethoxy)pyr imi din-4- yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid
55g (S)-8-(2-amino-6-((R)-l-(4-(benzo[d]isoxazol-6- 570
yl)p enyl)-2,2,2-ti fluoiOethoxy)pyrimidin-4-yl)- 2 , 8 -diazaspiro [4.5] decane -3 -carb oxy 1 ic acid
55h (S)-8-(6-((R)- 1 -(4-(lH-indazol-6-yl)phenyl)- 569
2,2,2-trifluoiOethoxy)-2-aminopyrimidin-4-yl)-
H r 2,8-diazaspiro[4.5]decane-3-carboxylic acid
55i (S)-8-(2-ammo-6-((R)-2,2J2-trifluoro-l-(4-(l - 583
methyl- 1 H-indazol-6-
/ r yl)phenyl)ethoxy)pyi'imidin-4-yI)-2,8- diazaspiro[4.5]decane-3-cai*boxylic acid
55j (S)-8-(2-amino-6-((R)- 1 -(4-(benzo[d]isothiazol- 586
5-yl)phenyl)~2,2,2-ti'ifluoiOethoxy)pyrimidin-4- yl)-2,8-diazaspiiO[4.5Jdecane-3-carboxylic acid
55k (S)-8-(2-amino-6-((R)-l-(4-(benzo[d]thiazol-6- 586
yl)phenyl)-2,2,2-trifluoroetlioxy)pyrimidin-4-yl)- 2,8-diazaspiiO[4,5]decane-3-cai'boxylic acid
551 (S)-8-(6-((R)-l -(4-([l,2,4]tnazolo[l,5-a]pyridin- 570
6-yl)phenyl)~2,2,2-trifluoiOethoxy)-2- aminopyriniidin-4-yl)-258-diazaspiiO[4.5]decane- 3-catboxylic acid
Figure imgf000243_0001
2,8-diazaspiiO[4.5]decane-3-carboxylic acid 5x (S)-8-(2-amino-6-((R)-l-(4-(l,3-dimethyl-lH- 597 indazoi-5-yl)phenyl)-2,2,2-
-' trifluoiOethoxy)pynmidin-4-yl)-2,8- diazaspii [4.5]decane-3-caiboxylic acid
5y (8)-8-(2-3ΐΏίηο-6-(( )-1-(4-(1 ,3-άίηΐ6 1-1Η- 596 indol-S-y^phenyl)^^^- trifluoiOethoxy)pyi'imidin-4-yl)-2,8- diazaspiiO[4.5]decane-3-carboxylic acid
5z (S)-8-(2-amino-6-((R)-2,2,2-trifluoiO-l-(3'- 627 methoxy-5'-(trifluoromethyl)-[ 1 , 1 '~biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2)8- diazaspiiO[4,5]decane-3-carboxylic acid
F
55aa (S)-8-(2-amino-6-((R)- 1 -(3'-cyano~5'-methoxy- 584
[l,l'-biphenyl]-4-yl)-2,2,2- tnfluoi'oethoxy)pyrimidin-4-yl)-2,8- diazaspir o [4.5 Jdecane- 3 -c arb oxy 1 ic acid
55ab (S)-8-(2-amino-6-((R)-2,252-tnfluoiO-l-(4-(2- 586
° X oxo -2,3 -dihy di obenzo [d] oxazol -6- yl)phenyl)ethoxy)pyrimidm-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
5 Sac (S)-8-(2-amino-6-((R)-2,2,2-trifl oiO-l~(4-(3- 1 methyl- 1 H-indo 1- 5 -yl)pheny 1) ethoxy)py rimidin- 4-y i)-2, 8-diazaspi ro [4.5 jdecane-3-carboxyi ic acid
5 Sad (S)-8-(6-((R)-l -(3,-acetoxy-4'- 645
0 O^O (methoxycarbonyl)-[l,r-biphenyl]-4-yi)-2,2,2- trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxyIic acid
55ae 0 (S)-8-(2-amino-6-((R)-2,2,2-trifluoiO-l-(4-(2- 596 oxo-2H-cliiOmen-7-yl)plienyl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
SSaf (S)-8-(2-amino-6-((R)-2,2,2-trifliioi -l -(4-(l - 560 methyl-6-oxo- 1 ,6-dihydropyridin-3- y l)phenyl) ethoxy)pyrimidi n-4 -y l)-2, 8 - diazaspiro[4.5]decane-3-carboxylic acid
55ag O HO (S)-8-(2-amino-6-((R)-l-(4'-carboxy-3"-hydiOxy- 588
H0X0 [l,l'-biphenyl]-4-yl)-2,2)2- trifluoi ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000245_0001
4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
Figure imgf000249_0001
co (8)-8-(2-αηαϊηο-6-(( )-2,2,2-ΐπΑΐΐθΐΌ-1-(3',4',5*- 583 tnfluoiO-[l,r-biphenyl]-4-yl)ethoxy)pyrimidin-4- yl)-2, 8 -diazaspiro [4.5]decane-3 -carboxylic acidcp (S)-8-(2-amino-6-((R)- 1 -(4'-chloiO-2'-methyl- 577
[U'-biphenyl]-4-yl)-2,2,2- tri fluoroethoxy)pyrim id in-4-y 1) -2, 8 - diazaspiiO[4.5]decane-3-carboxylic acid
cq (8)-8-(2^ηιίηο-6-((Κ)-1-(3',5'-άϊηΊ6 1-[1}1'- 557 biphenyl]-4-yl)-2,2,2-trifl\ioiOet oxy)pyiimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acidcr (S)-8-(2-ammo-6-((R)-l-(3')4,-difluoro-[ljr- 565 biphenyl] - 4 -y 1) -2,2,2-trifluoroethoxy)py rimi din- 4-yl)-2,8-diazaspiro[4,5]decane-3-carboxylic acidcs (S)-8-(2-amino-6-((R)"l -(2',5,-dimethyl-[l}l'- 557 biplienyl]-4-yl)-2,2,2-trifluoroethoxy)pyiimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid ct (S)-8-(2-araino-6-((R)-l-(4,-butyl-[l,l,-biphenyI]- 585
4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4.5]decane-3 -carboxylic acid
cu (S)-8-(2-amino-6-((R)~2,2,2-trifluoi -l-(3'- 561 fluoiO-4'-methyl-[l, -biphenyl]-4- yl)ethoxy)py r i m idin- 4-y 1) -2 , 8 - diazaspiiO[4.5]decane-3-carboxylic acid
cv o (S)-8-(2-amino-6-((R)-2,2,2-trifluoiO-l-(4'- 607
(methylsul fony 1) - [ 1 , -biphenyl] -4 - yl)ethoxy)pynmidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid
cw (S)-8-(2-amino-6-((R)-2,2i2-trifluoiO-l-(4'- 543 methyl-[l , 1 '-biphenyl]-4-yl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acidcx (S)-8-(2-amino-6-((R)-2,2J2-trifluoro-l-(3'- 543 methyl-[l , 1 '-biphenyl]-4-yl)ethoxy)pyrimidin-4- yl) -2, 8-di azaspiro [4.5] dec ane-3 -c arb oxylic acidcy (S)-8-(2-amino-6-(( )-l-(4,-chlol -[l ,l,- 563 biphenyl]-4-yl)-2i2}2-tnfluoroetrtoxy)pynmidin- 4-yI)-2,8-diazaspiiO[4.5]decane-3-carboxylic acidcz (S)-8-(2-amino-6-((R)-l-(4-(benzofuran-3- 569 yl)phenyl)-252,2-tnfluoiOethoxy)pyrimidin-4-yl)- 2,8-diazaspiiO[4.5]decane-3-carboxylic acid
Figure imgf000251_0001
Figure imgf000252_0001
Table 17b.
NMR Data for Compounds of Table 17a
Figure imgf000252_0002
H), 6.61 (m, 1 H), 5.56 (m, 1 H), 4.07 (m, 1 H), 3.90 (s, 3 H), 3.63 (m, 2 H), 3.48 (m, 2 H), 3.25 (m, 1 H),3.13 (m, 1 H), 2.30 (m, 1 H), 2.04 (m, 1 H), 1.60 (s, 4 H)
f lH NMR (400 MHz, DMSO-d6): δ ppm 9.09 (s, 1 H), 8.45 (s, 1 H), 8.26 (m, 1 H), 7.83-7.77(m, 3 H), 7.64 (m, 2 H), 6.73 (m, IH), 6.06 (s,lH), 5.57 (s.lH), 3.45 (m, 4H), 2.99 (m, 2 H), 2.10 (m, 1 H), 1.79 (m, 1 H), 1.42 (m, 4 H).
g Ή NMR (400 MHz, MeOH-d4): 8 ppm 7.66-7.56 (m, 6H), 7.19-7.17 (m, 2H), 6.66 (q, J = 6.7 Hz, 1H), 5.56-5,55 (m, 1H), 4.08 (m,lH), 3.64-3.59 (m, 2H), 3.53-3.43 (m, 2H), 3.23-3.13 (m, IH), 2.98-2,92 (m, IH), 2.35-2.19 (m, 1H), 2.08-2.03 (m, H), 1.59 ( m, 4H).
Ή NMR (400 MHz, MeOH-d4): 8 ppm 8.06 (s, IH), 7.83 (d, J = 8.3 Hz, IH), 7.73 (d, J = 7.7 Hz, 3H), 7.62 (d, J = 7.5 Hz, 2H), 7.44 (d, J = 8.6 Hz, IH), 6.67 (q, J = 7.4 Hz, IH), 5.58 (s, IH), 4.08 (m,lH), 3.69-3.61 (m, 2H), 3.52-3.43 (m, 2H), 3.23-3.10 (m, 2H), 2.35-2.30 (m, IH), 2.08-2.03 (m, IH), 1.60 (s, 4H).
i ¾ NMR (400 MHz, DMSO-d6): 8 ppm 8.03 (s, 1 H), 7.83-7.82 (d, 2 H, J=4.5 Hz), 7.81 -7.79 (d, 2 H, J=7.6 Hz), 7.62-7.60 (d, 2 H,J=7.6 Hz), 7.43-7.41 (d, 2 H, J=8.6 Hz), 6.71-6.70 (q, 1 H, J=6.8 Hz), 5.55 (s, 1 H), 4.02 (s, 3 H), 3.71 (m, 1 H), 3.55-344 (m, 4 H), 2.85 (m, 1 H), 2.12 (m, 1 H), 1.71 (m, 1 PI), 1.40 (m, 4 H).
j Ή NMR (400 MHz, MeOH-d4): 8 ppm 8.96 (s, 1 H), 8.33 (s, 1 H), 8.09-8.07 (d, 1 H, J=8.8 Hz), 7.81-7.79(dd, 1 H, J=8.0 Hz), 7.71-7.69 (d, 2 H, J=8.0 Hz), 7.60-7.58 (d, 2 H, J=8.0 Hz), 6.63-6.58 (q, 1 H),5.51 (s.lH), 4.00-3.96 (m, 1 H), 3.57 (m, 2 H), 3.40 (m, 2 H), 3.17-3.14 (d, 1 H, J=11.7 Hz), 3.13-3.00 (d, 1 H, J=l 1.7 Hz), 2.23-2,21 (m, 1 H), 1.99-1.94 (m, 1 H), 1.53 (m, 5 H).
k Ή NMR (400 MHz, MeOH-d4): δ ppm 9.26 (S, 1 H), 8.33 (s, 1 H), 8.13-8.11 (d, 1 H, J=8.5 Hz), 7.84-7.82(dd, 1 H, J=8.5 Hz), 7.76-7.74 (d, 2 H, J=8.3 Hz), 7.65-7.63 (d, 2 H, J=8.3 Hz), 6.67-6.65 (q, 1 H, J=7.2 Hz), 4.15-4.11 (m, 1 H), 3.53 (m, 2 H), 3.49 (m, 2 H), 3.27-3.24 (d, 1 H, J=11.7 Hz), 3.15-3.12 (d, 1 H, J=l 1.7 Hz), 3.33-2.31 (m, 1 H), 2.07-2.03 (m, 1 H), 1.61 (m, 5 H).
1 'H-NMR (400 MHz, MeOH-d4); δ ppm 9.08 9(s,lH) , 8.44 (s,lH) ,8.02 -8.03
(m,lH),7.83 -7.86 (m, 2H), 7,66 -7.75 (m, 2H),6,66 -6.69 (m,lH),5,50 (s,lH),4.07 - 4.07 (m, 1H),3.64 -3.66 (m, 2H), 3.44 -3.48 (m, 2H), 3,19 -3.24 (m,lH), 3.16 -3.46 (m,lH), 2.29 -2.55 (m,lH), 2.03 -2.08 (m,lH), 1.60 -1.61 (m,4H)
m 'H-NMR (400 MHz, DMSO-d6): 8 ppm 8.19 (s,lH), 7.84 -7.97 (m,6H), 7.63 -7.82 (m, 2H), 7.50 -7.61 (m, 2H), 6.70 -6.76 (m,lH), 5.58 (s,lH), 3.38 -3.47 (S, IH), 3.00 - 3.00 (m, 1H),2.91 -2.94 (m,lH), 2,06 -2.13 (m,lH), 1.74 -1.78 (m,lH), 1.37 -1.44 (m,4H)
n 'H-NMR (400 MHz, MeOH-d4): δ ppm 7.63-7.65 (m,2H), 7.56 -7.58 (m, 2H), 7.15 - 7.20 (m, IH), 7.07 -7.09 (m, 2H), 6.60 - 6.65 (m,lH), 4.11 -4.16 (m,lH), 3.87 (s, 3H), 3.48 -3.66 (m, 4H), 3.23 -3.26 (m, IH), 3.11 -3.16 (m,lH), 2.31 -3.41 (m,lH), 2.20 (s,3H), 2.02 -2.10 (m,lH), 1.59 -1.61 (m,4H), 1.27 -1.31 (m,lH)
o Ή NMR (400 MHz, MeOH-d4): 8 ppm 7.62-7.56 (m,4H), 7.00 (s,lH), 6.93 (sJH) 6.74(s,lH), 6.64 (q, IH, J=8.0), 5,56 (d, IH, J=4.0), 4.08-4.04 (m, IH), 3.80 (s, 3H), 3.63 (s, 2H), 3.47 (s, 2H) 3.23 (d, IH, J = 16.0), 3.10 (d, IH, J = 12.0 Hz), 2.36 (s, 3H), 2.04 (s, I H), 1.59 (s, IH), 1.28 (s, IH)
p Ή NMR (400 MHz, MeOH-d4): 8 ppm 0.89 (m, IH), 1.30 (d, J = 15.5 Hz, 3H), 1.62 (d, J = 5.7 Hz, 5H), 2.06 (m, IH), 2.14 (s, 3H), 2.33 (dd, J = 13.5, 9.2 Hz, IH), 3.13 (d, J = 11.7 Hz, IH), 3.25 (d, J = 1 1.3 Hz, IH), 3.51 (dt, J = 20.9, 6.7 Hz, 2H), 3.66 (d, J = 13.3 Hz, 2H), 3.76 (s, 3H), 4.09 (t, J - 8.2 Hz, IH), 5.57 (s, IH), 6.69 (m, 2H), 6.81 (dd, J = 8.4, 2.8 Hz, IH), 7.15 (d, J = 8.4 Hz, IH), 7.35 (m, 2H), 7.57 (d, J = 7.9 Hz, 2H)
q 'H NMR (400 MHz, MeOH-d4): δ ppm 7.62 (d52H,J=8.0), 7.56(d,2H,J=8.0),
7.18(m,2H), 7.02(d,l H,J=8.0), 6.62 (q, 1H,J=8.0), 5.55 (s, IH), 4.01-3.97 (m, IH), 3.31-3.23 (m, IH), 3.89 (s, 31-1), 3.86 (s, 3H), 3.67-3.60 (m, 2H),3.49-3.43 (m, 2H) 3.19 (d, IH, J - 12.0), 3.02 (d, IH, J = 12.0 Hz),2.27(dd, IH, J = 12.0,8.0), 2.00 (dd, IH, J = 14,0,4.0), 1.58 (s, 1H),1.28 (s, IH)
r Ή NMR (400 MHz, MeOH-d4): δ ppm 7.70-7.61 (m, 4H), 7.28 (m, 3H), 6.67 (q, J - 7.6 Hz, IH), 5.56 (s, IH), 4.08 (m,lH), 3.91 (s, 3H), 3,63-3.46 (m, 8H), 3,13 (m, IH), 2.35-2.29 (m, IH), 2.01-1.99 (m, IH), 1.97-1.87 (m, 5H), 1.59 ( m, 4H).
s Ή-NMR (400 MHz, MeOH-d4): δ ppm 1.74-1.73 (m,4H), 2, 13-2.07 (m,lH), 2.52- 2.46 (m,lH), 3.60-3.55 (m, IH), 3.70-3.66 (m,2H), 4.55-4.50 (m,lH), 5.44 (s,2H), 6.66-6,63 (m,lH), 7.74-7,69 (m,2H), 7,88-7.80 (m,4H), 7.96-7.92 (m,lH)
t Ή NMR (400 MHz, MeOH-d4): δ ppm 8.03 -8.05 (m,lH) ,7.95 (s, IH), 7.84 -7.86 (m,lH), 7,71 -7.73 (m, 2H), 7.60 -7.62 (m, 2H),7.43 -7.45 (m, IH), 6.62 -6.65 (m, 2H), 5.57 (s, IH), 4,05 -4.10 (m,lH), 3.61-3.70 (m,3H), 3.42 -3.52 (m, 3H), 3.09 -3,12 (m, IH), 2.29 -2.36 (m,lH), 2.02 -2.07 (m, IH), 1.60 (m, 4H)
u Ή NMR (400 MHz, DMSO-d6): δ ppm 8.02 (s,lH), 7,93 -7.98 (m, 2H), 7.76 -7.78 (m, 2H), 7.59 -7.63 (m, 3H), 6.63 -6,73 (m, 2H), 5,55 (s, IH), 3,74 -3.79 (m,lH), 3.61 (s,3H), 3.32 -3,47 (m, 5H), 2.89 -3.07 (m,2H), 2.08 -2, 14 (m,lH), 1.73 -1.80 (m, IH), 1.41 (m, 4H).
v Ή NMR (400 MHz, MeOH-d4): δ ppm 7.62(d,2H,J=8.0), 7.56 (d,2H,J=8.0), 7.45 (m,2H), 6.93 (d)lH,J=8.0), 6.62 (q, 1H,J=8.0), 5.56 (s, IH), 4.07 (t, IH, J=8.0), 3,64δ3.58 (m, 2H), 3.52-3.45(m, 2H), 3.24 (d, IH, J = 12.0),3.11 (d, IH, J = 8.0 Hz), 3.01 (t, 2H, J = 8.0 ), 2.59-2.57 (m, 2H), 2.32(dd, IH, J = 12.0,8.0),2.05(dd, IH, J = 12.0,8.0), 1.58 (s, 4H),1.28 (s, IH)
w !H MR (400 MHz, DMSO-d6): 6 1 ,59 (m, 4 H), 2.05-2.01 (m, 1 H, J=11.6 Hz), 2.32- 2.28 (m, 1 H, J=1 1.6 Hz), 3.11-3.08 (d, 1 H), 3.25-3.22 (d, 1 H), 3.50-3.47 (m, 2 H), 3,68-3.65 (m, 2 H), 4.08-4.04 (q,l H), 5.57 (s, 1 H), 6.66-6.65 (q, 1 H), 8.10 (s, 1 H), 7.61-7.60 (m, 3 H, J=8.6 Hz), 7.71-7.69 (m, 3 H, J=8.6 Hz), 8.01 (s, 1 H)
x 'H NMR (400 MHz, MeOH-d4): δ ppm 1.61 (d, J = 5.7 Hz, 4H), 2.06 (dd, J = 13.5, 7.3 Hz, IH), 2.35 (dd, J = 13,5, 9,2 Hz, H), 2.56 (s, 3H), 3.15 (d, J = 11 ,8 Hz, IH), 3.25 (d, J = 1 i .7 Hz, IH), 3.54 (m, 5H), 3.99 (s, 3H), 4.17 (t, J - 8.3 Hz, IH), 5.00 (s, H), 6.66 (q, J = 7.1 Hz, IH), 7.53 (d, J - 8.8 Hz, IH), 7.61 (d, J = 8.1 Hz, 2H), 7.70 (m, 3H), 7.91 (s, IH)
y ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.54 (m, 4 H), 2.10 (m, 1 H), 2.26 (m, 4 H), 3.04 (m, 1 H), 3.17 (m, 1 H), 3.40 (m, 2 H), 3.56 (m, 2 H), 3.69 (s, 3 H), 4.07-4.03 (m, 1 H), 6,65-6.59 (m, 1 H), 6.93 (s, 1 H), 7.37-7,34(m, 1 H), 7.45-7.42 (m, 1 H), 7.57- 7.55 (m, 2 H), 7.72-7.68 (m, 3 H)
z lH NMR (400 MHz, MeOH-d4): δ ppm 7.72-7.63(m,4H), 7.45(s,lH), 7.40 (s,lH), 7.18 (s,lH), 6.66 (q, IH, J=8.0), 4.30 (d, IH, J=8.0), 3.91 (s, 3H), 3.66 (s, 2H),3.55(s, 2H), 3,26 (s, IH), 3.19(d, IH, J = 12.0 Hz), 2.43-2,37 (m, IH), 2.10-2,05 (m, IH), 1.65 (s, 5H), 1.28 (s, IH)
aa ¾ NMR (400 MHz, MeOH-d4): δ ppm 7.94 (d,lH,J=4.0), 7.71 (d,lH,; 4.0), 7.53- 7.50 (m,2H), 6.82 (q,lH,J=8.0), 6.41 (d, 1H,J=4.0), 5.68 (d, 1H,J=4.0), 4.41 (s, IH), 3.09 (s, 1H), 2.75(t, 2H, J=8.0 ), 2.46 (d, 1 H, J=16.0), 2.38 (s, 3H),2.22(dd, 1H, J = 16.0,8.0), 1.23-1 .19 (m, 3H)
ab H NMR (400 MHz, MeOH-d4): δ ppm 1.60 (m, 4 H), 2.03-2.05 (m, 1 H), 2.33-2.32 (m} 1 H), 3.14-3.1 1 (d, 1 H, J=l 1.9 Hz), 3.26-3.23 (d, 1 H, J=1 1.9 Hz), 3.52-3.47 (m, 2 H), 3.65-3,54 (m, 2 H), 4.10-4.06 (m, IH), 5.57 (s, 1 H), 6.65-6.64 (q, 1 H), 7.16-7.14 (d, 2 H, J=8.2 Hz), 7.51 -7.44 (dd, 2 H, J=8.2 Hz), 7.51 (s, 1 H), 7.60-7,57 (d, 2 H, J 8.3 Hz), 7.65-7.63 (d, 2 H, J=8.3 Hz)
ac Ή NMR (400 MHz, MeOH-d4): δ ppm 7.72-7,69 (m, 3 H), 7.58-7.56 (m, 2 H), 7.38 (s, 2 H), 7,02(m, 1 H), 6.61 (m, 1 H), 4.23(m, 1 H), 3.65 (m, 2 H), 3.48 (m, 2 H), 3.30 (m, 1 H), 3.14 (m, 1 H), 2. 31 (m, 4H), 2.06 (m, 3 H), 1 ,62 (s, 4 H).
ad 'H MR (400 MHz, MeOH-d4): δ ppm 8.08 (d, J = 8,2 Hz, 1H), 7,77 (d, J = 8.2 Hz, 2H), 7.67-7.65 (m, 3H), 7.46 (m, 1H), 6.67-6.61 (m, IH), 4.47 (m, I H), 3.87 (s, 3H), 3.73-3.52 (m, 4H), 3.27-3.22 (m, 2H),2,50-2.44 (m, IH), 2.33 (s, 3H), 2.12-2,06 (m, IH), 1.68 (m, 4H).
ae Ή NMR (400 MHz, DMSO-d6): δ ppm 1 ,22 (d, J = 5.3 Hz, 2H), 1.42 (m, 4H), 1.82 (d, J = 13.2 Hz, IH), 1.98 (dd, J = 17.4, 8.5 Hz, IH), 2.91 (to, IH), 3.03 (d, J = 1 1 ,0 Hz, IH), 3.55 (s, IH), 3.68 (s, IH), 3.80 (s, IH), 5.62 (s, IH), 6.13 (s, 2H), 6.49 (d, J = 9.6 Hz, IH), 6,75 (q, J = 7.3 Hz, IH), 7.67 (m, 4H), 7.83 (dd, J = 22.1 , 8.1 Hz, 3H), 8.09 (d, J = 9,5 Hz, IH)
af ¾ NMR ( 400 MHz, MeOH-d4): δ ppm 8.01 (d,J=2.6Hz, IH) ,7.89(dd, J=2,72, 6.8 Ηζ,ΙΗ), 7.58(m,4H), 6.64(m, 2H),5.56(s, lH),4.08(m, lH) ,3.64(s,3H),3.53(m, 4H),3.12(m, 2H), 2.33(mslH),2.06(m, lH), 1.60(m,4H).
ag Ή NMR (400 MHz, MeOH-d4): δ ppm 7.92 (d, J = 8.8 Hz, IH), 7.65 (dd, Jl = 8.4 Hz, J2 - 31.9Hz, 4H), 7.17-7.14 (m, 2H), 6.66-6.63 (m, IH), 4, 14-4.10 (m, IH), 3.66-3,59 (m, 2H), 3.54-3.43 (m, 2H), 3.26-3.24 (m, IH), 3.15-3.12 (m, H), 2.37-2.32 (m, IH), 2.08-2.03 (m, IH), 1.61 (m, 4H)
ah ¾ NMR (400 MHz, MeOH-d4): δ ppm 8.16 (d,J = 8.92 Ηζ, ΙΗ), 8.02 (d,J=l .56 Hz, lH),7.93-7.86 (m,2H), 7.76 (d,J=8.16 Hz, 2H), 7.64(d,J=8.08 Hz,2H),6.96 (d,J = 8.88 Ηζ,ΙΗ), 6,66 (q, J = 7.12 Ηζ,ΙΗ), 5.57(s, lH), 4.06(s,3H), 3.97 (m, IH), 3.64(m, 2H), 3.47(m,2H), 3.17 (d, J=10.92 Ηζ,Ι Η), 3.00 (d, J=12.04 Ηζ,ΙΗ), 2.26 (m, IH), 2.0 l(m, IH), 1.58 (s, 4H)
ai Ή NMR (400 MHz, MeOH-d4): δ ppm 8.06 (d, J = 8.76 Ηζ,ΙΗ), 8.01 (s, 1H),7.93 (s ,2H),7.76 (d, J = 8.04 Hz, 2H),7.64 (d, J = 8.16 Hz, 2H), 7.31 (d, J = 8.76 Hz, IH), 6.68 (q, J = 8.48 Hz, I H), 5.58 (s, I H), 4.08 (m, IH), 3.63-3.50 (m, 4H), 3.24 (d, J = 1 1.64 Hz, IH), 3.12 (d,J = 1 1.64 Ηζ, ΙΗ), 2.68(s, 3H), 2.31 (m, IH), 2.05 (m, IH), 1.59 (m, 4H).
aj Ή NMR (400 MHz, MeOH-d4): δ ppm 67.67(d,2H,J=8.0), 7.61 -7.57(m,4H),
7.51(s,lH), 7.20(d!lH,J=8.0), 6.63 (q, 1 H,J=8.0), 4.29 (t, IH, J=12.0), 3.6763.58 (m, 2H), 3,53-3,48(111, 2H), 3.38(s,3H), 3,27 (d, IH, J = 12.0),3.19 (d, H, J = 8.0 Hz), 2.99-2.95 (m, 2H), 2,65-2.63 (m, 2H), 2.40(dd, IH, J = 12.0,8.0),2.09(dd, I H, J = 12.0,8.0), 1.66 (s, 5H),1.31 (s, 2H)
ak Ή NMR (400 MHz, MeOH-d4): δ ppm 1.52 - 1.67 (m, 4 H) 2.05 (dd, J=13.42, 7.13 Hz, 1 H) 2.32 (dd, J=13.54, 9.30 Hz, 1 H) 3.07 - 3.16 (m, 1 H) 3.24 (d, J=1 1.76 Hz, 1 H) 3.38 - 3.55 (m, 2 H) 3.56 - 3.76 (m, 2 H) 4.10 (t, J=8.18 Hz, 1 H) 5.56 (s, 1 H) 6.63 (q, 5=6.96 Hz, 1 H) 7.06 (qd, J=5.74, 3.29 Hz, 1 H) 7.35 (dd, JM9.30, 1.44 Hz, 1 H) 7.38 - 7.48 (m, 2 H) 7.55 - 7.69 (m, 4 H) 5al Ή NMR (400 MHz, MeOH-d4): δ ppm 1.59 (d, J=4.59 Hz, 4 H) 2.04 (dd, J=13.50, 7.30 Hz, 1 H) 2.31 (dd, J=13.30, 9.01 Hz, 1 H) 3.05 - 3.25 (m, 2 H) 3.37 - 3.53 (m, 2 H) 3.54 - 3.69 (m, 2 H) 3.81 (s, 3 H) 4.05 (dd, J=9.18, 7.32 Hz, 1 H) 5.54 (s, 1 H) 6.61 (q, J=7.29 Hz, 1 H) 6.89 (dd, J=7.83, 2.12 Hz, 1 H) 7.05 - 7,21 (m, 2 H) 7.26 - 7.38 (m, 1 H) 7.46 - 7.68 (m, 4 H)
5am Ή NMR (400 MHz, McOH-d4): δ ppm 1.63 (d, J=5.08 Hz, 4 H) 2.08 (dd, J=13.32, 7.18 Hz, 1 H) 2.35 (dd, J=13.32, 9.22 Hz, 1 H) 3.07 - 3.20 (m, 1 H) 3.27 (d, J=11.71 Hz, 1 H) 3.40 - 3.58 (m, 2 H) 3.59- 3.80 (m, 2 H) 4.1 1 (t, 1=7.96 Hz, 1 H) 5.58 (s, 1 H) 6.68 (d, J=7.13 Hz, 1 H) 7.10 (dt, J=6.00, 2.95 Hz, 1 H) 7.38 (d, J=10.35 Hz, 1 H) 7.42 - 7.52 (m, 2 H) 7.56 - 7.79 (m, 4 H)
San Ή NMR (400 MHz, MeOH-d4): δ ppm 1.48 - 1.66 (m, 4 H) 2.01 (dd, 1=13.37, 7.17 Hz, 1 H) 2.28 (dd, J=13.35, 9.20 Hz, 1 H) 3.06 (d, J=11.71 Hz, 1 H) 3.20 (d, J=l 1.67 Hz, 1 H) 3.35 - 3.52 (m, 2 H) 3.53 - 3.69 (m, 2 H) 3.81 (s, 3 H) 4.02 (dd, J=9.15, 7.20 Hz, 1 H) 5.53 (s, 1 H) 6.61 (q, J=7.21 Hz, 1 H) 6.89 (dd, J=8.20, 2.49 Hz, 1 H) 7.06 - 7.21 (m, 2 H) 7.26 - 7.38 (m, 1 H) 7.47 - 7.68 (m, 4 H)
5ao 'H NMR (400 MHz, MeOH~d4): δ ppm 1.63 - 1.87 (m, 4 H) 2.10 (dd, J=13.72, 8.69 Hz, 1 H) 2.48 - 2.62 (m, 1 H) 3.33 (s, 0 H) 3.52 - 3.81 (m, 4 H) 3.84 (s, 3 H) 4.55 (t, J=8.81 Hz, 1 H) 5.93 (s, 0 H) 6.59 (d, J=6.25 Hz, 1 H) .71 (dt, J-10.75, 2.26 Hz, 1 H) 6,90 - 7.02 (m, 2 II) 7.51 - 7.80 (m, 4 H).
5ap 'H NMR (400 MHz, MeOH-d4): δ ppm 1.63 - 1.85 (m, 4 H) 2.10 (dd, J=13,64, 8.66 Hz, 1 H) 2.50 (dd, J=13.64, 8.81 Hz, 1 H) 3.51 - 3.88 (m, 5 H) 4.55 (t, J=8.71 Hz, 1 H) 5.93 (s, 1 H) 6.63 (q, J=6.61 Hz, 1 H) 6.96 (tt, J=9.06, 2.31 Hz, 1 H) 7.20 - 7.33 (m, 2 H) 7.62 - 7.80 (m, 4 H).
5aq ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.60 - 1.87 (m, 4 H) 2.09 (dd, J=13.64, 8.76 Hz, 1 H) 2.50 (dd, J-13.59, 8.86 Hz, 1 H) 3.51 - 3.79 (m, 4 H) 3.81 (s, 3 H) 4.56 (t, J=8.74 Hz, 1 H) 5.88 - 5.99 (m, 1 H) 5.93 (s, 1 H) 6.57 (d, J=6.39 Hz, 1 H) 6,94 - 7.04 (m, 2 H) 7.50 - 7.70 (m, 6 H)
5ar !H NMR (400 MHz, MeOH-d4): δ ppm 1.67 - 1.87 (m, 4 H) 2.10 (dd, J=13.64, 8.71 Hz, 1 H) 2.51 (dd, J=13.59, 8.86 Hz, 1 H) 3.54 - 3.77 (m, 4 H) 3.78 (s, 4 H) 4.57 (t, J=8.76 Hz, 1 H) 5.95 (s, 1 H) 6.59 (q, J=6.22 Hz, 1 H) 7.00 (td, J=7.46, 0.95 Hz, 1 H) 7.06 (d, J=8.10 Hz, 1 H) 7.19 -7.38 (m, 2 H) 7,48 - 7.66 (m, 4 H)
5as Ή NMR (400 MHz, MeOH-d4): δ ppm 1.60 - 1.86 (m, 4 H) 2.10 (dd, J=13.64, 8.66 Hz, 1 H) 2.50 (dd, J=13.62, 8.83 Hz, 1 H) 3.53 - 3,87 (m, 4 H) 4.54 (t, J=8.71 Hz, 1 H)
5.93 (s, 0 H) 6.64 (q, J=6.65 Hz, 1 H) 7.61 - 7.72 (m, 4 PI) 7.73 - 7.80 (m, 2 H) 7.84 -
7.94 (m, 2 H)
Sat 'H NMR (400 MHz, MeOH-d4): δ ppm 1.67 - 1.84 (m, 4 H) 2.10 (dd, J=13.67, 8.69 Hz, 1 H) 2.51 (dd, J=13.69, 8.81 Hz, 1 H) 3.55 - 3.82 (m, 4 H) 4.56 (t, J=8.76 Hz, 1 H) 5.95 (s, 1 H) 6.63 (q, J=6.56 Hz, 1 H) 7.29 (dt, J=8.1 , 1.15 Hz, 1 H) 7.48 - 7.58 (m, 2 H) 7,61 - 7.76 (m, 5 H)
5au ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.39 (t, J=7.00 Hz, 3 H) 1.65 - 1.86 (m, 4 H) 2.09 (dd, J=13.64, 8.76 Hz, 1 H) 2.50 (dd, J=13.62, 8.79 Hz, 1 H) 3.51 - 3.84 (m, 4 H) 4.07 (q, J=6,98 Hz, 2 H) 4.57 (t, J=8,74 Hz, 1 H) 5.94 (s, 1 H) 6.61 (q, J=6.57 Hz, 1 H) 6.82 - 6.95 (m, 1 H) 7.06 - 7.20 (m, 2 H) 7.28 - 7.43 (m, 1 H) 7.55 - 7.73 (m, 4 H)5av !H NMR (400 MHz, MeOH-d4): δ ppm 1.32 (d, J=6.05 Hz, 6 H) 1.65 - 1.86 (m, 4 H) 2.09 (dd, J=13.67, 8.69 Hz, 1 H) 2.50 (dd, J=13.64, 8.86 Hz, 1 H) 3.48 - 3.85 (m, 4 H) 4.55 (t, J=8.71 Hz, 1 H) 4.65 (dt, J=12.08, 6.06 Hz, 1 H) 5.92 (s, 1 H) 6.59 (q, J=6.43 Hz, 1 II) 6.91 (dd, J=8.22} 1.93 Hz, 1 H) 7.1 1 (t, J=2.03 Hz, 1 H) 7.15 (d, J=7.71 Hz, 1 H) 7.29 - 7.39 (m, 1 H) 7.56 - 7.73 (m, 4 H)
5aw 'H MR (400 MHz, MeOH-d4): δ ppm 1.62 - 1.93 (m, 4 H) 2.1 1 (dd, J=13.69, 8.76 Hz, 1 H) 2.54 (dd, J=13.69, 8.86 Hz, 1 H) 3.46 - 4.00 (m, 4 H) 4.59 (t, J=8.74 Hz, 1 H) 6.01 (s, 1 H) 6,74 (q, J=6.65 Hz, 1 H) 7.75 - 8.02 (in, 4 H) 8.20 (dd, J=8.22, 5.78 Hz, 1 H) 8.87 (d, J=5.71 Hz, 1 H)8.97 (dt, J=8.27, 1.72 Hz, 1 H) 9.24 (d, J=2.00 Hz, 1 H) Sax ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.64 - 1.90 (m, 4 H) 2, 1 1 (dd, J=13.67, 8.79 Hz, 1 H) 2.52 (dd, JM13.64, 8.86 Hz, 1 H) 3.49 - 4.02 (m, 4 II) 4.57 (t, J=8.71 Hz, 1 H) 6.01 (s, 1 H) 6.76 (d, J=6.54 Hz, 1 H) 7,85 (d, J=8.35 Hz, 2 H) 8.09 (d, J=8.49 Hz, 2 H) 8,33 - 8.54 (m, 2 H) 8.80 - 8.99 (m, 2 H)
5ay 'H NMR (400 MHz, MeOH-d4): δ ppm 1.56 - 1 .91 (m, 4 H) 2.10 (dd, J=13.69, 8.66 Hz, 1 H) 2.51 (dd, J=13.81, 8.83 Hz, 1 H) 3.53 - 3.94 (m, 5 H) 4.56 (dt, J=8.48, 4.37 Hz, 1 H) 5.89 - 6.14 (m, 1 H) 6.51 - 6,82 (m, 1 H) 7.48 - 8.01 (m, 4 H) 9.19 (s, 1 H) 9.24 (s, 1 H)
5az Ή NMR (400 MHz, MeOH-d4): δ ppm 1.60 (t, J=5.08 Hz, 4 H) 2.00 (s, 2 H) 2.03 - 2.13 (m, 1 H) 2.26 - 2,39 (m, 1 H) 2.52 - 2.64 (m, 4 H) 3.07 - 3.18 (m, 1 H) 3,26 (d, J=1 1.71 Hz, 1 H) 3.39 - 3.57 (m, 2 H) 3.57 - 3.77 (m, 2 H) 4.01 - 4.20 (m, 1 H) 5,58 (s, 1 H) 6.67 (s, 1 H) 7.40 (dd, J=8.49, 1.07 Hz, 1 H) 7.59 - 7.68 (m, 3 H) 7.69 - 7.79 (m, 3 H)
5ba ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.47 - 1.74 (m, 4 H) 1 .99 - 2, 13 (m, 1 H) 2.26 - 2.40 (m, 1 H) 2,55 (s, 3 H) 3.07 - 3.19 (m, 1 H) 3.21 3.29 (m, 1H) 3.48 (d, J=4.88 Hz, 2 H) 3.65 (d, J=3.32 Hz, 2 H) 4.01 (s, 3 H) 4.10 (dd, J=8.98, 7.22 Hz, 1 H) 5.59 (s, 1 H) 6,69 (d, J=7.03 Hz, 1 H) 7.41 (dd, J=8.49, 1.07 Hz, 1 H) 7.58 - 7.70 (m, 3 H) 7,70 - 7.84 (m, 3 H)
5bb Ή NMR (400 MHz, MeOH-d4): δ ppm 1.58 (br. s., 4 H) 1.95 - 2.09 (m, 1 H) 2.24 - 2.38 (m, 1 H) 2.63 (s, 3 H) 3.01 - 3.14 (m, 1 H) 3.17 3,25 (m, 1 H) 3.38-3.54 (m, 2 H) 3.55-3.74 (m, 2H)
5bc Ή NMR (400 MHz, MeOH-d4): δ ppm 1.62 (br. s., 4 H) 1.97 - 2.09 (m, 1 H) 2.24 - 2.36 (m, 1 H) 3.07 (s, 3 H) 3.18 - 3.27 (m, 1 H) 3.55 (s, 4 H) 3.60 - 3.75 (m, 2 H) 3.96 - 4.07 (m, 1 H) 5.59 (s, 1 H), 6,61 - 6,75 (m, 1 H) 7,54 - 7.61 (m, 1 H) 7.66 (s, 3 H) 7.72 (s, 2 H) 7.95 - 8,08 (m, 1 H)
5bd Ή NMR (400 MHz, MeOH-d4): δ ppm 1.50 - 1.68 (m, 4 H) 1.86 - 2.01 (m, 1 H) 2.1 1 - 2.28 (m, 1 H) 2.77 - 2.91 (m, 1 H) 3.04 - 3.13 (m, 1 H) 3.40 - 3.57 (m, 2 H) 3.59 - 3.74 (m, 2 H) 3.76 - 3 ,88 (m, 1 H) 5.54 - 5.66 (m, 1 H) 6.61 - 6.79 (m, 1 H) 7.67 - 7.77 (m, 2 H) 7.81 - 7.97 (m, 3 H) 7.99 - 8.09 (m, 1 H) 8.16 - 8.27 (m, 2 H) 8.41 - 8.53 (m, 1 H) 9.21 - 9.33 (m, l H)
5be lE NMR (400 MHz, MeOH-d4): δ ppm 1.50 - 1.65 (m, 4 H) 1.92 - 2.00 (m, 1 H) 2.14 - 2.28 (m, 1 H) 2.84 - 2.94 (m, 1 H) 3.04 - 3.16 (m, 1 H) 3,40 - 3.57 (m, 2 H) 3.58 - 3.73 (m, 2 H) 3.79 - 3.91 (m, 1 H) 5.59 (s, 1 H) 6.62 - 6,78 (m, 1 H) 7.64 - 7.75 (m, 2 H) 7.86 (d, J=8.59 Hz, 3 H) 8.01 - 8.09 (m, 1 H) 8.10 - 8.20 (m, 1 H) 8.35 - 8.42 (m, 1 H) 8,43 - 8.48 (m, 1 H) 9.25 - 9.37 (m, 1 H)
5bf lU NMR (400 MHz, MeOH-d4): δ ppm 1 ,61 (br. s„ 4 H) 1.94 - 2.04 (m, 1 H) 2,28 (s, 7 H) 2.92 - 3.06 (m, 1 H) 3.1 1 - 3.23 (m, 1 H) 3.53 (s, 4 H) 3.59 - 3.75 (m, 2 H) 3.89 - 4.02 (m, 1 H) 5,58 (s, 1 H) 6.60 - 6.70 (m, 1 H) 7.43 (s, 2 H) 7.57 - 7.74 (m, 6 H)5bg lK NMR (400 MHz, MeOH-d4): δ ppm 1 .56 (d, J=4.69 Hz, 4 H) 1.78 - 1.95 (m, 1 H) 2.07 - 2.22 (m, 1 H) 2.69 - 2.83 (m, 1 H) 2.96 - 3.09 (m, 1 H) 3.38 - 3.54 (m, 2 H) 3.56 - 3.69 (m, 2 H) 3.70 - 3.79 (m, 1 H) 5.57 (s, 1 H) 6.59 - 6.77 (m, 1 H) 7.51 - 7.61 (m, 1 H) 7.68 (d, J=8.00 Hz, 2 H) 7.83 (d, J=8.20 Hz, 2 H) 8.11 (s, 2 H) 8.20 (s, 1 H) 8.38 - 8.50 (m, 1 H) 8.77 - 8.92 (m, 1 H)
bh 'H NMR (400 MHz, MeOH-d4): 8 ppm 1.57 (br. s„ 4 H) 1.84 - 2.03 (m, 1 H) 2.12 - 2.29 (m, 1 H) 2.91 (s, 1 H) 3.04 - 3.16 (m, 1 H) 3.38 - 3.55 (m, 2 H) 3.56 - 3.73 (m, 2 H) 3.78 - 3.96 (m, 1 H) 5.58 (s, 1 H) 6.60 - 6.80 (m, 1 H) 7.47 - 7.58 (m, 1 H) 7.69 (d, J=8.20 Hz, 2 H) 7.83 (d, J-8.20 Hz, 2 H) 7.93 (d, J=1.17 Hz, 1 H) 8.02 (d, J=8.59 Hz, 1 H) 8.25 (s, 1 H) 8.37 (s, 1 H) 8.87 (d, J=2.93 Hz, 1 H)
bi Ή NMR (400 MHz, MeOH-d 4): δ ppm 1.56 (d, J=5.08 Hz, 4 H) 1.76 - 1.88 (m, 1 H) 2.05 - 2.20 (m, 1 H) 2.63 - 2.81 (m, 1 H) 2.94 - 3.07 (m, 1 H) 3.37 - 3.54 (m, 2 H) 3.55 - 3.79 (m, 3 H) 5.58 (s, 1H) 6.61 - 6.78 (m} 1 H) 7.71 (d, J=8.20 Hz, 2 H) 7.86 (d, J=8.40 Hz, 2 II) 8.17 (s, 2 H) 8.32 (s, 1 H) 8.89 (dd, J=12.98, 1.66 Hz, 2 H)
bj Ή NMR (400 MHz, MeOH-d4): δ ppm 1.54 - 1.72 (m, 4 H) 2.01 - 2.13 (m, 1 H) 2.27 - 2.41 (m, 1 H) 3.06 - 3.16 (m, 3 H) 3.18 (s, 3 H) 3.22 - 3.30 (m, 1 H) 3.41 - 3.59 (m, 2 H) 3.67 (s, 4 H) 4.02 - 4.16 (m, 1 H) 5.53 - 5.66 (m, 1 H) 6.61 - 6.74 (m, 1 H) 7.54 - 7.57 (m, 1 H) 7.61 - 7.67 (m, 3 H) 7.70 - 7.80 (m, 2 H) 7.96 - 8.06 (m, 1 H)
bk Ή NMR (400 MHz, MeOH-d4): δ ppm 1.54 - 1.72 (m, 4 H) 2.05 - 2.18 (m, 1 H) 2.29 - 2.43 (m, 1 H) 3.08 - 3.20 (m, 1 H) 3.24 - 3.29 (m, 1 H) 3.43 - 3.76 (m, 4 H) 4.05 - 4.17 (m, 1 H) 5.57 - 5.67 (m, 1 H) 6.64 - 6.79 (m, 1 H) 7.65 - 7.76 (m, 2 H) 7.83 - 7.94 (m, 2 H) 8,08 - 8.19 (m, 1 H) 8.32 - 8.48 (m, 2 H) 9.21 - 9.33 (m, 1 H) 9.56 - 9.67 (m, 1 H)bp ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.60 (q, J = 5.9, 5.2 Hz, 4H), 1.98 (m, 5H), 2.32 (dd, J = 13.4, 9.3 Hz, 1H), 3.12 (d, J = 11.8 Hz, 1H), 3.25 (d, J = 11.7 Hz, 1H), 3.50 (m, 4H); 3.61 (m, 4H), 4.08 (dd, J = 9.2, 7.2 Hz, 1H); 5.57 (s, 1H), 6.67 (q, J = 7.1 Hz, 1H), 7.61 (ddd, J = 356.8, 7.9, 5.7 Hz, 4H), 7.71 (m, 4H)
cc !H NMR (400 MHz, MeOH-d4): δ ppm 0.09 (d, J = 1.2 Hz, OH), 1.28 (s, OH), 1.61 (q, J = 5.3 Hz, OH), 1.92 (m, OH), 2.05 (dd, J = 13.3, 7.3 Hz, OH), 2.32 (m, OH), 3.10 (s, OH), 3.29 (s, 2H), 3.53 (s, OH), 3.65 (s, 1H), 3.80 (dd, J = 16.8, 1.2 Hz, OH), 4.07 (t, J - 8.2 Hz, OH), 4.89 (d, J = 3.8 Hz, OH), 5.56 (d, J = 1.2 Hz, OH), 5.99 (m, OH), 6.60 (m, OH), 7.21 (dd, J - 8.4, 1.2 Hz, OH), 7.48 (d, J = 1.2 Hz, 1H)
ce 'H NM (400 MHz, DMSO-d6): δ ppm 1.58 (q, J = 6.7, 6.1 Hz, 4H), 1.94 (dd, J = 13.2, 9.1 Hz, 1H), 2.39 (dd, J = 13.3, 8.6 Hz, 1H), 3.20 (s, 2H), 3.80 (m, 3H), 4.54 (t, J = 8.4 Hz, 1H), 5.74 (s, 1H), 6.31 (s, 2H), 6.90 (q, J = 7.2 Hz, 1H), 7,49 (t, J = 6.5 Hz, 3H), 7.76 (m, 6H), 9,01 (dt, J = 21.8, 11.9 Hz, 1H), 9.74 (d, J = 11.9 Hz, 1H)cg Ή NMR (400 MHz, DMSO-d6): δ ppm 1.59 (m, 4H), 2.00 (s, 7H), 2,41 (m, 1H), 3.20 (s, 2H), 3,60 (m, 4H), 3.83 (m, 1H), 4.53 (d, J = 8.7 Hz, 1H), 5.74 (s, 1H), 6.34 (dd, J = 28.1, 14.7 Hz, 2H), 6.91 (q} J = 7.4 Hz, 1H), 7.24 (m, 5H), 7.67 (d, J = 7.8 Hz, 2H), 8.99 (s, 1H), 9.77 (d, J = 8.4 Hz, 1H)
cj Ή NMR (400 MHz, DMSO-d6): δ ppm 1.29 (d, J = 6.8 Hz, 6H), 1,58 (m, 4H), 1 ,94 (dd, J = 13.2, 9.2 Hz, 1H), 2.39 (dd, J = 13.4, 8.6 Hz, 1H), 2.99 (hept, J = 7.1 Hz, 1H), 3.19 (s, 2H), 3,59 (m, 4H), 4.55 (d, J = 9,2 Hz, 1H), 5,73 (s, 1H), 6,28 (m, 2H), 6,81 (q, J = 7.4 Hz, 1H), 7.41 (d, J = 7.9 Hz, 2H), 7.65 (m, 4H), 7.78 (d, J = 8.0 Hz, 2H), 8.97 (d, J = 13,6 Hz, 1H), 9.76 (s, 1H)
ck Ή NMR (400 MHz, DMSO-d6): δ ppm 0.99 (s, 1H), 1 ,31 (d, J = 6.9 Hz, 7H), 1.58 (m, 4H), 1.94 (dd, J = 13.2, 9.2 Hz, 1H), 2.39 (dd, J = 13.4, 8.6 Hz, 1H), 3.02 (hept, J = 7.2 Hz, 1H), 3.19 (s, 2H), 3.55 (ddd, J = 19.7, 12.2, 5.9 Hz, 2H), 3.86 (s, 2H), 4.05 (s, 1H), 4.54 (q, J = 8.9, 6,7 Hz, 1H), 5.73 (s, 1H), 6.31 (m, 2H), 6.81 (q, J = 7.3 Hz, 1H), 7.46 (m, 5H), 7.65 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 8.96 (dt, J = 20.8, 8.6 Hz, IH), 9.77 (d, J - 8.5 Hz, IH)
cp ]H NMR (400 MHz, DMSO-d6): δ ppm 1.29 (s, IH), 1.57 (dd, J = 9.4, 5.0 Hz, 12H), 1.94 (dd, J = 13.3, 9.1 Hz, 3H), 2.28 (s, 9H), 2.41 (m, 4H), 2.61 (d, J = 7.4 Hz, IH), 3.19 (s, 7H), 3.59 (m, 13H), 4.15 (s, IH), 4.55 (d, J = 8.4 Hz, 4H), 5.75 (s, 3H), 6.38 (m, 5H), 6.87 (q, J = 7.4 Hz, 3H), 7.46 (m, 22H), 8.98 (m, 3H), 9.76 (m, 3H)cq !H NMR (400 MHz, MeOH-d4): δ ppm 1.60 (m, 4H), 2.05 (m, IH), 2.34 (s, 7H), 3.12 (d, J = 11.5 Hz, IH), 3.24 (d, J = 11.5 Hz, IH), 3.49 (m, 2H), 3.64 (dq, J = 12.6, 6.5, 4.7 Hz, 2H), 4.08 (t, J = 8.2 Hz, IH), 5.56 (s, IH), 6.64 (q, J = 7.1 Hz, IH), 6.99 (s, IH), 7.21 (s, 2H), 7.59 (m, 5H)
cr 'H NMR (400 MHz, DMSO-d6): 5 ppm 1.29 (s, IH), 1.58 (dq, J = 11.6, 7.5, 7.1 Hz, 11H), 1 ,94 (dd, J = 13.3, 9.1 Hz, 3H)} 2.15 (s, OH), 2.39 (dd, J = 13.3, 8.6 Hz, 3H), 2.61 (d, J - 8,8 Hz, 3H), 3.05 (s, OH), 3, 19 (s, 6H), 3.40 (s, IH), 3.54 (h, J = 6.4 Hz, 3H), 3.81 (m, 4H), 4.01 (dd, J = 19.9, 11.7 Hz, lH), 4.16 (s, IH), 4.54 (t, J = 8.6 Hz, 3H), 5.73 (s, 3H), 6.28 (d, J = 15.5 Hz, 5H), 6.81 (q, J = 7.3 Hz, 3H), 7.63 (m, 1 IH), 7.86 (dd, J = 17.4, 7.8 Hz, 8H), 8.99 (dq, J = 23.7, 15.7, 12.4 Hz, 2H), 9.72 (s, 3H)cs 'H NMR (400 MHz, DMSO-d6): δ ppm 1.57 (m, J = 8.0, 6.2 Hz, 8H), 1.94 (dd, J = 13.2, 9.2 Hz, 2H), 2.23 (s, 6H), 2.34 (s, 8H), 3.20 (s, 5H), 3.57 (dp, J - 22.0, 7.4, 6.0 Hz, 9H), 4.54 (t, J = 8,4 Hz, 3H), 5.76 (s, 2H), 6.34 (d, J = 14.9 Hz, IH), 6.45 (s, IH), 6.86 (q, J = 7.4 Hz, 2H), 7.18 (m, 6H), 7.56 (dd, J = 46.1 , 7.8 Hz, 8H), 8.99 (m, 2H), 9.77 (d, J = 15.0 Hz, 2H)
ct ¾ NMR (400 MHz, DMSO-d6): δ ppm 0.97 (t, J = 7.3 Hz, 3H), 1.50 (m, 9H), 1.94 (dd, J = 13.3, 9.2 Hz, IH), 2.39 (dd, J = 13.3, 8.6 Hz, IH), 2.67 (q, J = 6.9, 6.2 Hz, 2H), 3.19 (s, 2H)} 3.57 (m, 5H), 3.85 (m, 1H)5 4.06 (d, J = 16.1 Hz, IH), 4.54 (m, IH), 5.74 (s, IH), 6.31 (s, 2H), 6,81 (q, J = 7.3 Hz, IH), 7.35 (d, J = 7.8 Hz, 2H), 7.64 (d, J = 7.8 Hz, 4H), 7,78 (d, J = 8.0 Hz, 2H), 8.96 (m, IH), 9.73 (d, J = 8.2 Hz, IH)
cv 'H NMR (400 MHz, DMSO-d6): δ ppm 1.29 (s, IH), 1.38 (s, IH), 1.58 (qd, J = 12.6, 8.1, 7.6 Hz, 1 IH), 1.95 (m, 8H), 2.43 (m, 5H), 2.94 (t, J = 10.0 Hz, IH), 3.08 (dd, J = 16.3, 7.0 Hz, IH), 3.19 (s, 6H), 3.33 (s, 8H), 3.52 (m, 4H), 3.82 (m, 5H), 4.11 (m, 4H), 4.53 (dt, J = 12.6, 6.0 Hz, 3H), 5.75 (s, 2H), 6.20 (s, IH), 6.28 (d, J = 9.3 Hz, 2H), 6.48 (s, 3H), 6.84 (q, J = 7.3 Hz, 2H), 7.56 (s, IH), 7.93 (m, 21H),
8.98 (dd, J = 13.6, 8.0 Hz, 2H), 9.71 (m, 2H)
cw !H NMR (400 MHz, DMSO-d6); δ ppm 1.29 (s, IH), 1.58 (dd, J = 7.3, 4.2 Hz, 8H), 1.94 (dd, J = 13.2, 9.1 Hz, 2H), 2.14 (d, J = 1.4 Hz, OH), 2.40 (s, 8H), 2,49 (d, J = 9.3 Hz, OH), 3.03 (m, I H), 3.19 (s, 5H), 3.55 (m, 3H), 3.81 (t, J = 8.1 Hz, OH), 4.00 (m, 8H), 4.24 (m, OH), 4,35 (m, IH), 4.54 (m, 2H), 5.74 (s, 2H), 6.31 (m, 3H), 6,80 (q, J = 7.3 Hz, 2H), 7.34 (d, J = 7.8 Hz, 4H), 7.64 (d, J = 8.1 Hz, 8H), 7.78(m, 4H), 8,99 (q, J = 8.5, 7.4 Hz, 2H), 9.74 (s, 2H)
cx 'H NMR (400 MHz, DMSO-d6): δ ppm 1.29 (s, IH), 1.59 (m, 11H), 1.94 (dd, J - 13.3, 9.1 Hz, 3H), 2.43 (s, 1 IH), 2.61 (d, J = 9.0 Hz, IH), 3.19 (s, 6H), 3.58 (m, 1 IH), 4.13 (s, IH), 4.54 (m, 6H), 5.75 (s, 2H), 6.26 (s, IH), 6.34 (s, IH), 6.42 (s, 2H), 6,81 (q, J = 7.3 Hz, 3H), 7.27 (d, J = 7.5 Hz, 3H), 7.58 (m, 20H), 8.98 (s, 3H), 9.77 (d, J = 9.9 Hz, 3H)
db ¾ NMR (400 MHz, MeOH-d4): 6 ppm 1.24 (m, 8H), 1.76 (dd, J = 12.6, .8 Hz, 9H), 2.01 (s, 3H), 2, 12 (m, 4H), 2.51 (dd, J = 13.6, 8.8 Hz, 3H), 2.63 (td, J = 7.6, 5.4 Hz, 4H), 2.90 (m, 6H), 3.36 (d, J = 12.8 Hz, 7H), 3.63 (dt, J = 11.5, 5.0 Hz, 4H), 3.76 (m, 4H), 4.11 (qd, J = 7.1, 3.6 Hz, 4H), 4.56 (t, J = 8.7 Hz, 3H), 4.94 (s, 2H), 6.62 (dq, J = 19.2, 6.7 Hz, 3H), 7.02 (dt, J = 6.2, 2.0 Hz, 3H), 7.16 (m, 2H), 7.38 (m, 2H); 7.65 (m, 9H), 7.84 (m, IH)
dc ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.58 (t, J = 5.4 Hz, 4H), 2.02 (dd, J = 13.4, 7.0 Hz, 1H), 2.29 (dd, J = 13.4, 9.1 Hz, IH), 3.08 (d, J = 1 1.6 Hz, IH), 3.21 (d, J = 11.5 Hz, IH), 3.46 (ddt, J = 20.6, 13.2, 5.7 Hz, 2H), 3.61 (d, J = 16.6 Hz, 2H), 4.05 (t, J = 8.1 Hz, IH), 4.94 (s, 10H), 5.58 (s, 1H)5 6.69 (q, J = 7.2 Hz, IH), 7.66 (d, J = 8.0 Hz, 2H), 7.79 (d, J - 7,9 Hz, 2H), 8.00 (dd, J = 8.9, 1.9 Hz, IH), 8.12 (m, 3H), 8.79 (d, J = 2.7 Hz, IH)
dd Hi NMR (400 MHz, MeOH-d4): δ ppm 1.05 (t, J = 7.4 Hz, 3H), 1.29 (d, J = 5.8 Hz, IH), 1.59 (q, J = 5.8, 5.0 Hz, 4H), 1.80 (h, J = 6.9 Hz, 2H), 2.04 (dd, J = 13.5, 7.1 Hz, IH), 2.32 (dd, J = 13.4, 9.2 Hz, IH), 3. 1 (d, J = 11.8 Hz, IH), 3.23 (d, J = 12.0 Hz, IH), 3.47 (ddt, J = 20.6, 13.1, 6.1 Hz, 2H), 3.64 (m, 2H), 3.96 (t, J = 6.4 Hz, 2H), 4.07 (dd, J = 9.1, 7.3 Hz, IH), 5.55 (s, IH), 6.62 (q, J = 7.1 Hz, IH), 6.97 (m, 2H), 7.56 (m, 6H)
de Ή NMR (400 MHz, MeOH-d4): δ ppm 1.15 (t, J = 7.0 Hz, 3H), 1.26 (t, J - 7.1 Hz, 3H), 1.61 (q, J = 5.9, 5.1 Hz, 4H), 2.05 (dd, J = 13.4, 7.2 Hz, IH), 2.32 (dd, J = 13.4, 9.2 Hz, 1 H), 3.11 (d, J = 11.8 Hz, IH), 3.24 (d, J = 1 1.6 Hz, IH), 3.35 (m, 3H), 3.56 (dddd, J = 47.5, 27.9, 14.5, 7.8 Hz, 6H), 4.07 (dd, J = 9.2, 7.1 Hz, 1H), 4.92 (s, 17H), 5.57 (s, IH), 6,66 (q, J = 7.1 Hz, IH), 7.46 (m, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.71 (m, 4H)
df !H NMR (400 MHz, MeOH-d4): δ pm 1.28 (s, IH), 1.64 (m, 4H), 2.07 (dd, J = 13.5, 7.6 Hz, IH), 2.39 (dd, J = 13.5, 9.0 Hz, IH), 3.17 (d, J = 11.7 Hz, IH), 3.27 (d, J = 12.0 Hz, 2H), 3.53 (dt, J = 22.9, 7.5 Hz, 2H), 3.67 (td, J = 13.8, 13,2, 6.4 Hz, 2H), 4.26 (t, J = 8.3 Hz, IH), 4.87 (m, 3H), 6.66 (q, J = 7,0 Hz, IH), 7.63 (d, J = 8.1 Hz, 2H), 7.74 (m, 4H), 7.96 (m, 2H)
dg Ή NMR (400 MHz, MeOH-d4): δ ppm 1.31 (dd, J = 17,3, 3.8 Hz, 2H), 1.62 (m, 4H), 2.06 (dd, J = 13.5, 7.4 Hz, 1H), 2.36 (dd, J = 13.5, 9.1 Hz, IH), 2.93 (s, 3H), 3.15 (d, J = 11.9 Hz, IH), 3.26 (d, J = 11.6 Hz, IH), 3.51 (m, 2H), 3.64 (dq, J = 12.1, 6.4, 5.1 Hz, 2H), 4, 18 (dd, J = 9.1, 7.5 Hz, IH), 4.93 (d, J = 1.7 Hz, 19H), 6.66 (q, J = 7.1 Hz, IH), 7.63 (d, J = 8.1 Hz, 2H), 7,72 (dd, J = 8,3, 5.9 Hz, 4H), 7.89 (m, 2H)
dh *H NMR (400 MHz, MeOH-d4): δ ppm 1.60 (q, J = 6.0, 5.0 Hz, 4H), 2.03 (dd, J = 13.4, 7.2 Hz, IH), 2.31 (dd, J = 13,4, 9.2 Hz, IH), 2.59 (dt, J = 24.2, 5,7 Hz, 6H), 3.10 (d, J - 11 ,7 Hz, IH), 3.23 (d, J = 1 1.9 Hz, IH), 3.62 (m, 10H), 4.06 (dd, J = 9.2, 7.2 Hz, IH), 4,87 (s, IH), 5.57 (s, IH), 6.66 (q, J = 7.1 Hz, IH), 7.62 (d, J = 8.1 Hz, 2H), 7.72 (m, 4H), 7.91 (m, 2H)
di lE NMR (400 MHz, MeOH-d4): S ppm 1.61 (d, J = 5.5 Hz, 4H), 2.05 (dd, J = 13.4, 7,1 Hz, IH), 2.32 (dd, J = 13.4, 9,3 Hz, lH), 3.15 (s, 4H), 3.25 (d, J = 11.6 Hz, 1H), 3.50 (dt, J = 20.2, 7.0 Hz, 2H), 3.64 (m, 2H), 4.09 (dd, J - 9.2, 7.1 Hz, IH), 5.58 (s, IH), 6.68 (q, J = 7.2 Hz, IH), 7.65 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 8.01 (m, 2H)
dj 'H MR (400 MHz, MeOH-d4): δ ppm 1.28 (s, IH), 1.60 (q, J - 6.4, 5.0 Hz, 4H), 2.03 (dd, J = 13.4, 7.1 Hz, 1H), 2.31 (dd, J = 13.4, 9.2 Hz, IH), 3.10 (d, J = 1 1.7 Hz, IH), 3.23 (d, J = 11.8 Hz, IH), 3.48 (m, 2H), 3.63 (m, 2H), 4.06 (dd, J - 9.2, 7.1 Hz, IH), 5.57 (s, IH), 6.67 (q, J = 7.1 Hz, IH), 7.68 (m, 4H), 7.79 (m, 2H), 7.96 (m, 2H)dk !H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (d, J - 3.6 Hz, IH), 1.63 (q, J = 5.8 Hz, 5H), 2.07 (dd, J = 13.5, 7.5 Hz, IH), 2.37 (dd, J = 13.5, 9.0 Hz, 1H), 3.04 (s, 3H), 3.15 (d, J = 24.6 Hz, 6H), 3.27 (m, IH), 3.52 (dt, J = 24.6, 8.3 Hz, 2H), 3.65 (m, 2H), 4,23 (t, J = 8.1 Hz, IH), 6.66 (q, J = 7.0 Hz, IH), 7.51 (d, J = 8.1 Hz, 2H), 7.68 (m, 6H) 5dl 'H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (m, 3H), 1.60 (q, J = 6.1 , 4.7 Hz, 4H), 2.05 (dd, J - 13.2, 7.0 Hz, IH), 2.32 (dd, J = 13.5, 9.2 Hz, IH), 3.13 (d, J = 1 1.6 Hz, IH), 3.26 (m, 5H), 3,48 (ddd, J = 26.8, 12,6, 5.3 Hz, 2H), 3.64 (td, J = 19.2, 16.1, 9.2 Hz, 2H), 3.78 (s, IH), 3.90 (m, 3H), 4.10 (dd, J = 9.2, 7.1 Hz, IH), 4.95 (s, 13H), 5.56 (s, IH), 6.67 (q, J = 7.0 Hz, IH), 7.67 (m, 7H)
55dm Ή NMR (400 MHz, MeOH-d4): δ ppm 1.06 (t, J = 7.4 Hz, 4H), 1.59 (d, J = 6.1 Hz, 5H), 1.82 (dq, J = 14.1 , 6.6 Hz, 2H), 2.02 (dd, J = 13.4, 7.2 Hz, IH), 2.30 (dd, J = 13.5, 9.2 Hz, IH), 3.07 (d, J = 11.6 Hz, IH), 3.21 (m, 2H), 3.48 (dt, J = 20.5, 6.6 Hz, 2H), 3.65 (d, J = 15.7 Hz, 2H), 4.03 (td, J = 7.7, 6.5, 5.1 Hz, 3H), 4.91 (m, IH), 5.55 (s, IH), 6.63 (q, J = 7.2 Hz, IH), 7.13 (t, J = 8.7 Hz, IH), 7.38 (m, 2H), 7.59 (q, J = 8.4 Hz, 4H)
55dn Ή NMR (400 MHz, MeOH-d4): δ ppm 1.28 (d, J = 2.6 Hz, IH), 1,43 (t, J = 6.9 Hz, 3H), 1.60 (q, J = 5.8 Hz, 4H), 2.05 (dd, J = 13.1, 7,0 Hz, IH), 2.33 (dd, J = 13.4, 9.0 Hz, IH), 3,12 (d, J = 11.4 Hz, IH), 3,25 (d, J = 1 1.4 Hz, IH), 3.48 (m, 2H), 3.65 (q, J = 12.5, 10.8 Hz, 2H), 4.11 (dq, J = 16.7, 8.5, 7.7 Hz, 3H), 5.56 (s, IH), 6.63 (q, J - 7.0 Hz, IH), 7.13 (t, J = 8.6 Hz, IH), 7.38 (m, 2H), 7.59 (q, J = 8.1 Hz, 4H)
55do Ή NMR (400 MHz, MeOH-d4): δ ppm 1.40 (t, J = 7.0 Hz, 3H), 1.60 (q, J = 5.9, 5.1 Hz, 4H), 2.05 (dd, J = 13.4, 7.2 Hz, IH), 2.33 (dd, J = 13.4, 9.2 Hz, IH), 3.12 (d, J = 1 1.7 Hz, lH), 3,24 (d, J = 11.7 Hz, IH), 3.47 (ddt, J = 20.2, 12.7, 5.6 Hz, 2H), 3.64 (m, 2H), 4.07 (p, J = 7.1 Hz, 3H), 5.56 (s, IH), 6.62 (q, J = 7.1 Hz, IH), 6.97 (m, 2H), 7.57 (m, 6H)
55dp lH NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, IH), 1.64 (d, J = 6.8 Hz, 5H), 2.07 (dd, J = 13,5, 7.6 Hz, IH), 2,38 (dd, J = 13.5, 9, 1 Hz, IH), 3.17 (d, J = 1 1.8 Hz, 1H), 3.27 (d, J = 1 1.8 Hz, IH), 3.52 (m, IH), 3.66 (m, IH), 4.24 (t, J = 8.3 Hz, IH), 6.70 (p, J = 7.2 Hz, IH), 7.72 (d, J = 8.1 Hz, 3H), 7.90 (m, 3H), 8.28 (m, 3H), 8.53 (m, IH), 9.31 (d, J = 5.9 Hz, IH)
55dq *H NMR (400 MHz, MeOH-d4): δ ppm 7.62 - 7.49 (m, 4H), 7.33 - 7.24 (m, 2H), 6.76 (d, J = 8.3 Hz, IH), 6.62 (q, J = 7.2 Hz, IH), 5.53 (s, IH), 4.19 - 4.12 (m, 2H), 4.08 (dd, J = 9,1, 7.3 Hz, IH), 3.61 (s, 2H), 3.44 (ddt, J = 20.8, 13.4, 6.0 Hz, 2H), 3.22 (d, J = 11.7 Hz, IH), 3.10 (d, J = 11.7 Hz, IH), 2.80 (t, J = 6.5 Hz, 2H), 2.30 (dd, J = 13.5, 9.2 Hz, IH), 2.00 (ddd, J = 17.2, 12.5, 6.7 Hz, 3H), 1.57 (q, J = 5.9, 4.6 Hz, 4H), 1.27 (s, IH)
Example 56: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4-(l,2,3,4-tetrahydroquinoxalin-6-yl) phenyl)ethoxy)pyrimidin-4- -2,8-diazaspiro[4.5]decane-3-carboxyIic acid
Figure imgf000261_0001
Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-2,2)2-trifliioro-l-(l,2}3,4-tetrahydiOquinoxalin-6- yl)ethoxy)pyrimidin-4-yl)-2}8-diazaspiro[4.5]decane-3-carboxylate (a by-product from the N- CBZ deprotection of Example 55bi) using the LiOH general method provided the title compound as an off-white solid.
Ή NMR (400 MHz, MeOH-d4): δ ppm 1.54 - 1.72 (m, 4 H) 2.07 - 2.14 (m, 1 H) 2.29 - 2.41 (m, 1 H) 3.09 - 3.18 (m, 1 H) 3.22 - 3.29 (m, 1 H) 3.36 - 3.42 (m, 4 H) 3.43 - 3.58 (m, 2 H) 3.60 - 3.80 (m, 2 H) 4.03 - 4.17 (m, 1 H) 5.49 - 5.65 (m, 1 H) 6.50 - 6.67 (m, 2 H) 6.77 - 6.92 (m, 2 H) 7.43 - 7.63 (m, 4 H), LCMS (MH+): 585.
Example 57: (S)-8-(2-amino-6-((R)-l-(3,4-dihydroquinazoIin-6-yl)-2,2,2- trifluoroethoxy)pyrimidin- -yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000262_0001
Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)- 1 -(3,4-dihydi quinazolin-6-yl)~2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate (a by-product from the N-CBZ deprotection of Example 55bk) using the LiOH general method provided the title compound as an off-white solid.
¾ NMR (400 MHz, MeOH-d4) δ ppm 1.54 - 1.66 (m, 4 H) 1.98 - 2.08 (m, 1 H) 2.23 - 2.34 (m, 1 H) 3.02 - 3.1 1 (m, 1 H) 3.17 - 3.25 (m, 1 H) 3.37 - 3.54 (m, 2 H) 3.55 - 3.72 (m, 2 H) 3.97 - 4.08 (m, 1 H) 4.62 - 4.70 (m, 2 H) 5.50 - 5.58 (m, 1 H) 6.56 - 6.66 (m, 1 H) 6.86 - 6.93 (m, 1 H) 7.19 - 7.24 (m, 1 H) 7.25 - 7.31 (m, 1 H) 7.38 - 7.44 (m, 1 H) 7.51 - 7.57 (m, 2 H) 7.57 - 7.64 (m, 2 H). LCMS (MH+): 583 Example 58: (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(l,2,3,4-tetrahydroquinazolin-6- yl)ethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000263_0001
Hydrolysis of (S)-ethyl 8-(2-amino-6~((R)- 1 -(354-dihydiOquinazolin~6-yl)-2,2}2- trifluoiOethoxy)pyrimidin-4-yl)-2f8-diazaspiro[4.5]decane-3-carboxylate (a by-product from the N-CBZ deprotection of Example 55bk) using the LiOH general method provided the title compound as an off-white solid,
Ή NMR (400 MHz, MeOH-d4) δ ppm 1.57 - 1.68 (m, 4 Η) 1.93 - 2.03 (m, 1 Η) 2,18 - 2.30 (m, 1 H) 2.90 - 3.01 (m, 1 Η) 3.12 - 3.19 (m, 1 Η) 3.43 - 3.75 (m, 4 Η) 3.86 - 3.95 (m, 1 H) 4.00 - 4.07 (m, 2 H) 4.15 - 4.23 (m, 2 H) 5.45 - 5.64 (m, 1 H) 6.56 - 6.67 (m, 2 H) 7.17 - 7.23 (m5 1 H) 7.27 - 7.33 (m, 1 H) 7.49 - 7.55 (m, 2 H) 7.55 - 7.62 (m, 2 H), LCMS (MH+): 585.
Example 59a: (S)-8-(2-amino-6-((R)-l-(4-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)-2,8-cliazaspiro[4.5]deca -3-carboxylic acid
Figure imgf000263_0002
N-CBZ Deprotection was carried out using Method B with (S)-8-(2-amino-6-((R)~l-(4- bi mophenyl)-2,252-trifluoi ethoxy) pyrimidin-4-yl)-2-(benzyloxycarbonyl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid (75 mg, product of Step 3, Example 55an) providing the title compound as a white solid. lH NMR (400 MHz, MeOH-d4): δ ppm 1.50 - 1.68 (m, 4 H) 1.96 (s, 2 H) 2.04 (dd, J=13.35, 7,20 Hz, 1 H) 2.31 (dd, J=13.35, 9, 10 Hz, 1 H) 3.07 - 3.26 (m, 2 H) 3.35 - 3.55 (m, 2 H) 3.55 - 3.73 (m, 2 H), 4.06 (dd, J=9.13, 7.17 Hz, 1 H) 5.52 (s, 1 H) 6.57 (q, J=7.11 Hz, 1 H) 7.41 (d, J=8.44 Hz, 2 H) 7.51 - 7.58 (m, 2 H); LCMS (MH+): 531.
Example 59b: (S)-8-(2-amino-6-((R)-2,2,2-trifluoiO-l-(naphthalen-2-yl)eihoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane- -carboxyIic acid
Figure imgf000264_0001
The title compound was made as described for Example lOe, starting with (R)-2}252-trifluoro-l- (naphthalen-2 -y l)ethanol . 'H N R (400 MHz, DMSO-d6): δ ppm 1.20 (dt, J = 12.5, 5.3 Hz, 2H), 1.47 (m, 3H), 1.88 (dd, J = 12.4, 8.0 Hz, 1H), 2.57 (s, 1H), 2.69 (s, 1H), 2.80 (d, J = 12.4 Hz, 1H), 3.36 (m, 3H), 3.97 (dt, J = 12.3, 5.2 Hz, 2H), 6.05 (s, 1H), 6.37 (m, 3H), 7.53 (m, 2H), 7.77 (dd, J = 7.5, 1.5 Hz, III), 7.93 (m, 4H); LCMS (MH+): 562. Example 59c: (S)-8-(2-amino-6-((R)-2(2,2-trifluoro-l-(4-(3-fluoroqiiinolin-6-yl)-2- methyIplienyl)ethoxy)pyrimidm-4-yi)-2>8-diazaspiro[4.5]decane-3-carboxy]ic acid
Figure imgf000264_0002
Step 1: To a solution of 4-bromo-2-methylbenzoic acid (5.0 g, 23.2 mmol) in DMF (50 mL) was added potassium carbonate (6.4 g,46.4 mmol) and iodomethane (6.6 g, 46,479 mmol). The mixture was stirred at RT for 12 h then diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo. Purification by normal phase silica gel column provided methyl 4-bromo-2-methylbenzoate as a colorless oil.
Step 2: To a solution of methyl 4-bromo-2-methylbenzoate (2 g, 8.7 mmol) in THF (20 mL) was added LAH (663 mg,17.5 mmol) at 0°C. The mixture was stirred at RT for 1 h, then diluted with NaOH (1 ,0M, 10 mL) and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo. Purification by normal phase silica gel column provided (4-bromo-2-methylphenyi)methanol as a colorless oil. Step 3: To the solution of (4-bromo-2-methylphenyl)methanol (1.8 g, 8.1 mmol) in CH2C12 (20 mL) was added Dess-Martin Periodinane (5,1 g, 12.1 mmol) at 0°C. The mixture was stirred at RT for 1 h, then diluted with water, and the solid was removed by filtration. The filtrate was extracted with CH2C12. The combined organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo. Purification by normal phase silica gel column provided 4-bromo-2- methylbenzaldehyde as a yellow oil.
Step 4: To a solution of 4-bromo-2-methylbenzaldehyde (1.5 g, 7.5 mmol) in THF (20 mL) was added TMSCF3 (2.2 g, 15.5 mmol) at 0°C and then TBAF (1.1 mL, 1.0 M in THF), The mixture was stirred at RT for lh, then diluted with HC1 (3.0 M, 10 mL), stirred at RT for 1 h and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over
Na2S04 and concentrated in vacuo. Purification by normal phase silica gel column provided l-(4- bromo-2-methylphenyl)-2,2,2-trifiuoi ethanoI as an off-white solid,
Step 5: To a solution of l-(4-biOmo-2-methylphenyl)-2,2,2-tiifluoiOethanol (1.8 g, 6.7 mmol) in CH2C12 (20 mL) was added Dess-Martin Periodinane (3.4 g, 8.1 mmol) at 0°C. The mixture was stirred at RT for 2 h, then diluted with water (10 mL) and filtered. The filtrate was extracted with CH2C12. The combined organic layer was washed with brine, dried over Na2S04 and
concentrated in vacuo. Purification by normal phase silica gel column provided l-(4-bromo-2- methylphenyl)-2,2,2-trifluoiOethanone as a yellow oil.
Step 6: Chiral reduction of l-(4-bi mo-2-methylphenyl)-2,2,2-trif uoiOethanone using the Iridium complex-catalyzed hydrogenation as described for Intermediate 1, (R)-l-(4-bromo-2-(3- methyl-lH-pyrazol-l-yl)phenyl)-2,252-trifluoroethanol provides (R)-l-(4-bromo-2- methylpheny l)-2 ,2 ,2-tri fluoro ethano 1. Steps 7; The title compound was prepared as described for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-
1- (3'-methoxy-[lj -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3- carboxylic acid (Example 55an) Steps 4-5. 3-Fluoro-6-(4,4,5,5-tetramethyl-lJ3)2-dioxaboiOlan-
2- yl)quinolone was used as the Suzuki coupling partner (CAS# 1251731-31-3). lH NMR (400 MHz, MeOH-d4): δ ppm 1.28 (s, 1H), 1.59 (s, 4H), 2.04 (dd, J - 13.5, 7.0 Hz, 1H), 2.31 (dd, J = 13.3, 9.3 Hz, 1H), 2.65 (s, 3H), 3.10 (d, J = 1 1.7 Hz, 1H), 3.23 (d, J = 11.5 Hz, 1H), 3.47 (t, J = 14.3 Hz, 211), 3.63 (t, J = 13.8 Hz, 2H), 4.07 (t, J = 8.1 Hz, 1H), 5.56 (s, 1H), 6.87 (q, J = 7.0 Hz, 1H), 7.63 (d, J = 4.6 Hz, 3H), 8.01 (d, J = 8.9 Hz, 1H), 8.12 (m, 3H), 8.80 (m, 1H). LCMS (MH+): 611.
Example 59d: (S)-8-(2-amino-6-((R)-l-(2-ethyl-4-(3-nuoroquinolin-6-yl)phenyl)-2}2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspjro[4,5]decane-3-carboxylic acid
Figure imgf000266_0001
Step 1: To a 0 °C solution of LDA (10.7 mL, 21 ,39 mmol) in THF (20 mL) was added 4-bromo- 2-methylbenzoic acid (2 g, 9.3 mmol) in THF (5 mL). The mixture was stirred at 0 °C for 1 h, cooled to -70 °C, and then Mel (2.3 mL, 37.20 mmol) was added dropwise. The mixture was allowed to warm up to 0 °C, stirred for 3 h, then quenched with H20, and the pH was adjusted to 1-2 with 3 N HCl. The mixture was then diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo. Purification by normal phase silica gel column provided 4-bromo-2-ethylbenzoic acid as a white solid. Step 2: The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-2,2}2- triiliioro-l-(4-(3-fiuoi quinolin-6-yl)-2-methylphenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid (Example 59c) starting with 4-bromo-2-ethylbenzoic acid in place of 4-bromo-2-methylbenzoic acid.
Ή NMR (400 MHz, MeOH-d4): δ ppm 1.29 (m, 1H), 1.41 (t, J = 7.5 Hz, 3H), 1.59 (q, J = 6.1, 5.6 Hz, 4H), 2.04 (dd, J = 13.5, 7.1 Hz, 1 H), 2.32 (dd, J = 13.4, 9.1 Hz, 1 H), 3.01 (dt, J = 12.1 , 7.0 Hz, 2H), 3.12 (d, J = 1 1.6 Hz, 1H), 3.24 (d, J = 1 1.8 Hz, 1H), 3.48 (dt, J = 21.5, 6.9 Hz, 2H), 3.62 (m, 2H), 4.08 (dd, J = 9.1, 7.0 Hz, 1H), 4.94 (s, 15H), 5.56 (s, 1H), 7.00 (q, J = 6.9 Hz, 1H), 7.67 (m, 3H), 8.11 (m, 5H), 8.80 (d, J = 2.8 Hz, 1H). LCMS (MH+): 626.
Example 60: 9-(2-Amino-6-((R)-l-(4-chLoro-2-(3-methyl-lH-pyrazoI-l-yl)phenyl)-2,2,2- trifluoroethoxy)pyrnnidin-4- l)-3,9-diazaspiro[5.5]undecane-2-carboxylic acid
Figure imgf000267_0001
Step 1: To a solution of methyl 3,9-diazaspiro[5,5]undecane-10-carboxylate (30 mg, 0.14 mmol) in dioxane (2 niL) / i-PrOH (2 mL) was added 4-chloro-6-[(lR)-l-[4-chloro-2-(3-methylpyrazol- l-yI)phenyl]-2,2,2-ti'ifluoiO-ethoxy]pyrimidin-2-amine (92 mg, 0.22 mmol), and the reaction was heated at 100 °C under microwave for 3 h. The reaction was cooled to RT, and concentrated in vacuo. The residue was purified by reversed phase HPLC (MeOH/H2O/0.5% TFA) to provide methyl 9-(2-amino-6-((R)-l-(4-chloro-2-(3-methyi- lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoiOethoxy)pyrimidin-4-yl)-3,9-diazaspiro[5.5]undecane-2-carboxylate as an off-white solid.
Step 2: Hydrolysis of methyl 9-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoiOethoxy)pynmidin-4-yl)-3,9-diazaspira[5.5]undecane-2-carboxylate using the LiOH general method provides the title compound as an off-white solid. Ή NMR (400 MHz, MeOH-d4): δ ppm 1.22 - 1.37 (m, 1 H) 1 ,30 - 1.30 (m, 1 H) 1.46 - 1.68 (m, 4 H) 1.68 - 1.90 (m, 2 H) 2.29 (dd, J=12.59, 6.83 Hz, 1 H) 2.37 (d, J=1.90 Hz, 3 H) 3.07 - 3.24 (m, 2 H) 3.59 - 3,90 (m, 4 H) 4.03 - 4.19 (m, 1 H) 6.29 - 6.38 (m, 1 H) 6,40 (d, J=2.29 Hz, 1 H), 6,88 - 7.02 (m, 1 H) 7.52 - 7.61 (m, 2 H) 7,65 - 7.74 (m, 1 H) 7.89 (d, J=2.34 Hz, 1 H). LCMS (MH+): 581.
Example 61: (S)-8-(2-Amino-6-((4-(3-methyl-lH-indazol-6-yl)phenoxy)methyl)pyrimidin-4- l)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000268_0001
Step 1: A mixture of 4-bromophenol (173 mg, 1.00 mmol), 4-chloro-6-(chloromethyl)pyrimidin- 2-amine (CAS#: 92311-35-8) (178 mg, 1.16 mmol) and K2CO3 ( 175 mg, 1.00 mmol ) in DMF (5 mL) was heated to 100°C for 12 h. The reaction was cooled to RT, concentrated in vacuo, and the residue taken up in and EtOAc. The organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo. Purification on normal phase silica gel (EtO Ac/petroleum ether) provided 4-((4-bromophenoxy)methyl)-6-chloropyrimidin-2-amine as a white solid.
Step 2: A mixture of 4-((4-Bromoplienoxy)methyl)-6-chloropyrimidin-2-amine (454 mg, 1.4 mmol), (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (500 mg, 1.44 mmol) and NaHC03( 605 mg,7 mmol ) in dioxane (5 mL) was heated to 100°C for 12 h. The reaction was cooled to RT, concentrated in vacuo, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04, and concentrated in vacuo. Purification on normal phase silica gel (EtOAc/petroleum ether) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6- ((4-biOmophenoxy)methyI)pyrimidin-4-yl)-258-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid. Step 3: To a solution of (S)-2~benzyl 3-ethyl 8-(2-amino-6-((4-bromophenoxy)methyi)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (550 mg, 0.9 mmol) in acetonitrile (5 mL) was added TMSI (705 mg, 3.5 mmol) dropwise at 0 °C. The mixture was stirred at 0 °C for 2 h, then concentrated in vacuo. The residue was dissolved in CH2C12 (20 mL) followed by the sequential addition of Et3N (267 mg, 2.6 mmol), and (BOQ2O (285 mg, 1.3 mmol). The reaction mixture was stirred at RT for 16 h then concentrated in vacuo. Purification on normal phase silica gel (CH2Cl2/MeOH) provides (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((4-bromophenoxy) methyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a light yellow solid. Step 4: A mixture of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((4-bromophenoxy)
methyl)pyrimidin-4-yi)-2,8-diazaspiiO[4.5]decane-2;3-dicarboxylate (350 mg, 0.56 mmol), 3- methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaboiOlan-2-yl)-lH-indazole (285 mg, 1,1 mmol) and Pd(dppf)Cl2 (62 mg, 0.09 mmol) in dioxane (5 mL)/aq. Na2C03 solution (2.0 M, 5 mL) was heated to 90 °C for 4 h. The reaction was cooled to RT, the solids filtered away, and the solution concentrated in vacuo. Purification on normal phase silica gel (CH2Cl2 MeOH) provided (S)-2- tert-butyl 3-ethyl 8-(2-amino-6-((4-(3-methyl-lH-indazol-6-yl)phenoxy)methyl)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a brown solid.
Step 5: To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((4-(3-methyl-lH-indazol-6- yl)phenoxy)methyi)pyrimidin-4-yl)-2,8-diazaspira[4.5]decane-2,3-dicarboxyIate (150 mg, 0.19 mmol) in CH2C12 (5 mL) was added TFA (3 mL), and the resulting mixture was stirred at RT for 1 h, The reaction mixture was concentrated in vacuo, and the resulting material partitioned bewteen CH2CI2 and saturated NaHC03j and extracted, The combined organic layers were dried over Na2S0 , filtered, and concentrated in vacuo. Purification by prep-TLC (CH2Cl2/MeOH) provided (S)-ethyl 8-(2-amino-6-((4-(3-methyl- lH-indazol-6-yl)phenoxy)methyl)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a brown solid.
Step 6: To a solution of (S)-ethyl 8-(2-amino-6-((4-(3-methyl-lH-indazol-6-yl)phenoxy)methyl) pyrimidin-4-yl)-2,8-diazaspiro 4.5]decane-3-carboxylate (70 mg, 0.11 mmol) in MeOH (3 mL) is added 4 N NaOH (3 mL), and the reaction mixture was stirred at RT for 4 h. The reaction mixture was then concentrated in vacuo. The residue was diluted with water (5 mL) and the pH adjusted to 6-7. The precipitated solid was collected by filtration, and the filter cake was washed with cold water, then dried to afford the title compound as an off-white solid.
!H MR (400 MHz, DMSO-d6): δ ppm 7.72-7,70 (d, 1 H), 7.61-7.59 (d, 3 H), 7.31-7.30 (d, 1 H), 7.06-7.04 (d, 2 H), 6.14 (s, 1 H), 4.76 (s, 2 H), 3.87-3.83 (q, 1 H), 3.46-3.41 (m, 4 H), 3.08- 3.06 (d, ί H), 2.98-2.95 (d, 1 H), 2.43 (s, 1 H), 2.16-2.13 (m, 1 H), 1.82-1.80 (m, 1 H), 1.44 (m, 4 H). LCMS (MH+): 514.
Example 62: (S)-8-(2-amino-6-((5-chloro-3,-(methyls Ifonyl)-[l,l'-biphenyl]-2- yl)metlioxy)pyrimidhi-4-yl -2,8-diazaspiro[4.5]decane-3-carboxylic acid
Figure imgf000270_0001
Step 1: A mixture of (2-bromo-4-chlorophenyl)methanol (173 mg, 1. mmol), 4-chloro-6- (chloromethyl)pyrimidin-2-amine (178 mg, 1 ,16 mmol) and K2CO3 ( 175 mg, 1.00 mmol ) in DMF (5 mL) was heated to 100 °C for 12 h. The reaction was cooled to RT, concentrated in vacuo, and extracted with EtO Ac. The combined organic layers were washed with brine, dried over Na2S0 , and concentrated in vacuo. Purification on normal phase silica gel
(EtO Ac/petroleum ether) provided 4-((2-biOmo-4-chlorobenzyl)oxy)-6-chloropyrimidin-2-amine as a white solid. Step 2: A mixture of 4-((2-biOmo-4-chlorobenzyl)oxy)-6-chloiOpyrimidin-2-amine (300 mg, 1 ,1 mmol), (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (400 mg, 1.2 mmol), and NaHC03( 550 mg,7 mmol ) in dioxane (5 mL) was heated to 100 °C for 12 h. The reaction was cooled to RT, concentrated in vacuo, and extracted with EtOAc. The combined organic layers were washed with brine, water, dried over Na2S0 , and concentrated in vacuo.
Purification on normal phase silica gel (EtOAc/petroleum ether) provided (S)-2-benzyl 3-ethyl 8- (2-amino-6-((2¾omo-4-chloiObenzyl)oxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-2,3- dicarboxylate as a white solid.
Step 3: To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((2-bromo-4- chloi benzyl)oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2}3-dicarboxylate (500 mgt 0.8 mmol) in acetonitrile (5 mL) was added TMSI (705 mg, 3.5 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h, then concentrated in vacuo. The residue was dissolved in CH2CI2 (20 mL), followed by the sequential addition of Et3N (267 mg, 2.6 mmol), and (BOC)20 (285 mg, 1.3 mmol). The reaction mixture was stirred at RT for 16 h, then concentrated in vacuo, Purification on normal phase silica gel (CH2Cl2/MeOH) provided (S)-2- tert-butyl 3-ethyl 8-(2-amino-6-((2-bi mo-4-chlorobenzyl)oxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-2J3-dicai'boxylate as a light yellow solid.
Step 4: A mixture of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((2-bromo-4-chloi'obenzyl) oxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-2,3-dicarboxylate (300 mg, 0.4 mmol), (3-
(methylsulfonyI)phenyl)boionic acid (280 mg, 1 mmol), and Pd(dppf)Ch (62 mg, 0.09 mmol) in dioxane (5 mL)/aq. Na2C0 solution (2.0 M, 5 mL) was heated to 90 °C for 4 h. The reaction was then cooled to RT, the solids filtered away, and the filtrate concentrated in vacuo.
Purification on normal phase silica gel (CH2Cl2/MeOH) provided (S)-2-tert-butyl 3-ethyl 8-(2- amino-6-((5-chloiO-3,-(methylsulfonyl)-[l,r-biphenyl]-2-yl)methoxy)pyrimidin-4-yl)-2,8- diazaspiro[4,5]decane-2,3-dicarboxylate as an off-white solid.
Step 5: To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((5-chloro-3'-(methylsulfonyl)- [l, -biphenyl]-2-yl)methoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (200 mg, 0.25 mmol) in CH2C12 (5 ml) was added TFA (3 mL), and the resulting mixture was stirred at RT for 1 h, The reaction mixture was concentrated in vacuo, and the residue was partitioned between CH2C12 and saturated NaHC03. The organic layer was dried over Na2S0 j filtered, and concentrated in vacuo. Purification by prep-TLC (CPkCb/MeOH) provided (S)-ethyl 8-(2- amino-6-((5-chloro-3'-(methylsulfonyl)-[l; -biphenyl]-2-yl)methoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate as an off-white solid. Step 6: To a solution (S)-ethyl 8-(2-amino-6-((5-chloiO-3'-(metliylsulfonyl)-[l,r-biphenyl]-2- yI)methoxy)pyrimidin-4-yl)"2,8-diazaspii [4.5]decane-3-carboxylate (100 mg> 0.13 mmol) in MeOH (3 mL) was added 4 N NaOH (3 mL), and the mixture was stirred at RT for 4 h. The reaction mixture was then concentrated in vacuo. The residue was diluted with water (5 mL) and the pH adjusted to 6-7. The precipitated solid was collected by filtration, the filter cake was washed with cold water, then dried to afford the title compound as an off-white solid isolated as the zwitterionic form. lK NMR (400 MHz, MeOH-d4): δ ppm 7.94 (m, 2 H), 7.59-7.57 (m, 3 H), 7.44-7.40 (m, 1 H), 7.33 (m, 1 H), 5.33 (m, 1 H), 4.07 (m, 1 H), 3.59 (m, 2 H), 3.45 (m, 2 H), 3.30 (m, 1 H), 3.15 (m, 1 H),2.32 (m, 1 H), 2.06 (m, 1 H), 1.61 (s, 4 H). LCMS (MH+): 573.
The following esters were isolated as either a TFA or HC1 salt formed during the HPLC purification procedure used to isolate the final compounds.
Example 63bd: (S)-ethyl 8-(2-amino-6-((R)-l-(3,,4,-dimethyl-3-(3-methyl-lH-pyrazol-l-yl)-
[l, -biphenyl]-4-yl)-2,2,2-trifIuoroethoxy)pyrimidin-4-yl)-2)8-diazaspiro[4.5]decane-3- carboxylate
Figure imgf000272_0001
A solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-l -(3,,4'-dimethyl-3-(3-methyl-lH-pyrazol- 1 -yl)-[l , r~biphenyl3-4-yl)-2,2,2-trifluoiO^
dicarboxylate (from Step 3, Example 1m, 220 mg, 0.3 mmol,) in EtOAc (5 mL) was
hydrogenated using Method A by using an H-Cube apparatus and a 10% (w/w) Pd/C cartridge with a flow rate of 1.0 mL/min at RT. Purification on normal phase silica gel (EtO Ac/heptane) provided (S)-ethyl 8-(2-amino-6-((R)-l -(3',4'-dimethyl-3-(3-methyl-l H-pyrazoi- 1 -yl)-[l , 1 biphenyl]-4-yl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate. Example 63kp: (S)-ethyl 8-(2-amiiio-6-((R)~2,2,2-trifluoro-l-(3'-(hydroxymethyl)-4'- methyl-3-(3-methyl-lH-pyrazol-l-yl)-[1 '-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decan -3-carboxylate
Figure imgf000273_0001
The title compound was prepared as described for (S)-ethyl 8-(2-amino-6-((R)-l-(3\4'-dimethyl- 3-(3-methyl- IH-pyrazol-l -yl)-[i , 1 l-biphenyl]-4-yl)-2J252-trifluoroethoxy)pyrimidin-4-yl)-2}8- diazaspiio[4.5]decane-3-carboxyIate (Example 63bd) using Method A to remove the N-CBz group.
Example 63i: (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-[l,l'-bipheiiyi]-2-yl)-2,2,2- trifluo]Oethoxy)pyrimidi -4-yI)-2,8-diazaspiro[4.5]dccane-3-carboxyIate
Figure imgf000273_0002
A solution of (S)-2-benzyI 3-ethyl 8-(2-amino-6-((R)-l-(5-chloro-[l)r-biphenyl]-2-yl)-2,2;2- trifluoiOethoxy)pyrimidin-4-yl)-2J8-diazaspiro[4.5]decane-2,3-dicarboxylate (from Step 3, Example 34c, 315 mg, 0.43 mmol) in acetonitrile (300 mL) was added TMSI (0.13 mL, 0.9 mmol) [Method B]. The reaction mixture was then warmed to RT for an additional 30-40 min, then cooled to 0-5 °C, and 2 M HCl in diethyl ether (0.5 mL) was added. The reaction mixture was the allowed to warm RT and then concentrated in vacuo. Normal phase silica gel chromatography provide the title compound as an off-white solid. Ethyl ester prodrugs in Table 18a were prepared by removing the N-CBZ group by either method A or method B, as shown below.
Figure imgf000274_0001
Table 18a.
Figure imgf000274_0002
Figure imgf000274_0003
d j (S)-ethyl 8-(2-amino-6-((R)-l-(5- chloro-4'-nitro-[l , 1 '-biphenyl]-2- y -2,2,2-
A ti'ifluoroethoxy)pyrimidin-4-yl)- 631
2,8-diazaspiro[4.5]decane-3- carboxylate
e (S)-ethyl 8-(2-amino-6-((R)-i-(4-
(benzo[d]isothiazol-5-yl)phenyl)-
2,2,2-trifluoiOethoxy)pyrimidin-4- yl)-2,8~diazaspiro[4.5]decane-3-
B carboxylate 613 f (S)-ethyl 8-(2-amino-6-((R)-l-(4~
(benzo[d]isothiazol-6-yl)phenyl)- 2,2;2-trifluoroethoxy)pyrimidin-4-
A yl)-2,8 -diazaspiro [4.5] decane-3 - 616 carboxylate
Figure imgf000275_0001
g (S)-ethyl 8-(2-amino-6-((R)-l-
(3',4'-dimethoxy-[l)r-biphenyl]-4- yl)-2,2,2-
A 616
†rifluoroethoxy)py ri m idin- 4-y 1) - 2, 8-diazaspiro[4.5] decane-3 - carboxylate
h (S)-ethyl 8-(2-amino-6-((R)-2,2,2- tfifluoi -l-(4-(l-methyl-2-oxo-
1 ,2-dihydroquinolin-6-
A 637 yl)phenyl)ethoxy)pyrirnidin-4~yl)-
2,8-diazaspiiO[4.5]decane-3- carboxylate
i (S)-ethyl 8-(2-amino-6-((R)-l-(5- chloro-[l, -biphenyl]-2-yl)-2}2,2-
Jy B trifluoiOethoxy)pyrimidin-4-yl)- 591
2, 8-diazaspiro [4.5]decane-3 - carboxylate
j (S)-ethyl 8-(2-amino-6-((R)-l-(3'- amino-5-chloro-[l , 1 '~biphenyl]-2- yi)-2,2,2-
B 606 tiifluoroethoxy)pyrimidin-4-yl)- 2,8 -diazaspiro [4.5]decane-3 - carboxylate
Figure imgf000276_0001
Figure imgf000277_0001
carboxylate
Figure imgf000278_0001
ae (S)-ethyl 8-(2-amino-6-((R 1 -(4- chloro~3'-(met ylsulfonyl)-[l ,Γ- biphenyl]-2-yl)-2,2,2-
B trifluoiOethoxy)pyrimidin-4-yl)- 668
2,8-diazaspiro[4.5]decane-3- carboxylate
CI
af 1 (S)-ethyl 8-(2-amino-6-((R> 1 -(5- o=s=o
chloiO-3'-(methylsulfonamido)-
[l,r-biphenyl]-2-yl)-2,2;2-
B trifluoroethoxy)pyrimidin-4-yl)- 683
2,8-diazaspiro[4.5]decane-3- carboxylate
ag Br (S)-ethyl 8-(2-amino-6-((R> 1 -(2- bi mo-5-chlorop enyl)-2,2,2-
B trifluoroethoxy)pyrimidin-4-yl)- 593
2,8-diazaspiro[4.5]decane-3- CI
carboxylate
ah (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoi -l-(4-(l-methyl-2-oxo- 1 ,2,3 ,4 -tetr ahy droquinol in-6 -
A 595 yl)phenyl)ethoxy)pyriinidin-4-yl)- 2}8-diazaspiro[4.5]decane-3- carboxylate (
ai (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-l-(4-(2-
(methylthio)quinolin-6-
A yl)phenyl)ethoxy)pyrimidin-4-yl)- 554
2,8-diazaspiro[4.5]decane-3- f carboxylate
aj Br (S)-ethyl 8-(2-amino-6-((R)-l- (2,5-dibiOmophenyl)-2,2,2-
B trifluoroethoxy)pyrimidin-4-yl)- 638 2, 8-diazaspii [4.5]decane-3 - Br
carboxylate
ak (S)-ethyl 8-(6-((R)-l -([1 , 1 ' :4',1
terphenyl]-2'-yl)-2,2,2- trifluoroethoxy)-2-
A 633 aminopyrimidin-4-yI)-2,8- diazaspiro[4.5]decane-3- carboxylate
al (S)-ethyl 8-(2-amino-6-((R)-l-(2*- (ethoxycai'bonyl)-3-(3-methyl-lH-
A pyrazol- l-yl)-p ,l'-biphenyl]-4- 708 yl)-2,2,2- trifluoiOethoxy)pyrimidin-4-yl)-
2,8-diazaspiro[4.5]decane-3- carboxylate
am (S)-ethyl 8-(2-amino-6-((R)-l-(3'- (ethoxycarbony 1)- 3 -(3 -m ethyl- 1 H- pyrazol- 1 -yl)-[l , -bip enyl]-4-
A yi)-2,2,2- 708 trifluoroethoxy)pyrimidin-4-yl)- 2 , 8 -diazaspiro [4.5 ]decane-3 - carboxylate
an (S)-ethyl 8-(2-amino-6-((R)-l -(4'- (ethoxycarbony 1)- 3 -(3 -methyl - 1 H- pyr azol - 1 -yl) - [ 1 , 1 '-biphenyl] - 4 -
A yl)-2,2,2- 708 tiifluoiOethoxy)pyrimidin-4-yl)- r° 2,8-diazaspii [4.5]decane-3- carboxylate
ao Br (S)-ethyl 8-(2-amino-6-((R)-l- (2,6 -dibromopheny l)-2,2 ,2- trifluoi ethoxy)pyrimidin-4-yl)-
B 638 2, 8 -diazaspi ro [4.5] decane- 3 - carboxylate ap (S)-ethyl 8-(2-amino-6-((R)-l- (3',5-dichloro-[l ,r-biphenyl]-2- yl)-2,2,2-
B 625 trifmoioethoxy)pyrimidin-4-yl)- 2, 8 -diazaspiro [4.5] decane- 3 - carboxylate
aq (S)-ethyl 8-(2-amino-6~((R)- 1 -(5- chloio-3'-methyl-[l , 1 '-biphenyl]- 2-yl)-2,2,2-
B 605 trifluoiOethoxy)pyrimidin-4-yl)-
2,8-diazaspiro[4.5]decane-3- carboxylate
ar (S)-ethyl 8-(2-amino-6-((R)-l-(5- chloro-3 '-(trifluoromethyl)-[ 1 , - biphenyl]-2-yl)-2,2,2-
B trifluoi'oethoxy)pyrimidin-4-yl)- 659
2;8-diazaspiro[4.5]decane-3- carboxylate
Figure imgf000281_0001
az (S)-ethyl 8-(2-amino-6-((R)-l-(4- chloro-2-(3 -methyl- 1 H-pyrazol - 1 - yl)phenyl)-2,2,2-
B triflvwroethoxy)pyrimidin-4-yl)- 594
.if 2,8 -diazaspii o[4.5]decane-3 - carboxylate ba (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro- 1 -(3'-methoxy-[ 1 , 1 '-
A biphenyl]-4-yl)ethoxy)pynmidin- 587 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
bb (S>ethyl 8-(2-amino-6-((R)-252,2- trifluoro- 1 -(4-methoxy-2-(3- methyl- 1 H-pyrazol- 1 -
A 591
J? yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
bc (S)-ethyl 8-(2-amino-6-((R)~2,2,2- tnfluoi -l-(3'-fluoi -[l}r- biphenyl]-4-yl)ethoxy)pyrimidin-
A 575
4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate bd (S)-ethy 1 8-(2-amino-6-((R 1 - (3^4'-dimethyl-3-(3-methyl-lH- pyrazol- 1 -yl)-[l , 1 '-biphenyl]-4- yl)-2,2,2-
A 665 trifluoroethoxy)pyrimidin-4-yl)-
2,8-diazaspiro[4.5]decane-3- carboxylate be (S)-ethyl 8-(2-amino-6-((R)-l-(4- ethyl-2-(3-methyl- lH-pyrazol-1 - yl)phenyl)-2,2,2-
Jf A trifluoiOethoxy)pyrimidin-4-yl)- 589
2,8 -diazaspiro[4, 5]decane-3 - carboxylate bf (S)-ethyl 8-(2-amino-6-((R)-2,2,2- tiifluoro-l -(2-(3-methyl- 1H- pyrazol-l-yl)-4-
A propylpheny 1) ethoxy)pyri midin- 4- 603 yl)-2, -diazaspiro [4,5] decane-3 - carboxylate
Figure imgf000283_0001
Figure imgf000284_0001
carboxylate
Figure imgf000285_0001
carboxylate bz (S)-ethyl 8-(2-amino-6-((R)-l-(4- (3 -ethoxy-3 -oxopropyl)-2-(3 - methyl- 1 H-pyrazol- 1 -yl)phenyl)-
A 660 2,2}2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
ca (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro-l~(4-(isoquhiolin-7-
A yl)phenyl)ethoxy)pyrimidin-4~yl)- 607
2,8-diazaspiro[4.5]decane-3- carboxyl te
cb (S)-ethyl 8-(2-amino-6-((R)- 1 -(5-
(4-ethoxy-4~oxobutyl)-2-(3- methyl- 1 H-pyrazol - 1 -yl)phenyl)-
A 674
2,2,2-trifliioroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3- catboxylate
cc (S)-ethyl 8-(2-amino-6-((R)- 1 -(4-
(4-ethoxy-4-oxobutyl)phenyl)-
252,2-trifIuoroethoxy)pyrimidin-4-
A yl)-2,8-diazaspiro[4.5]decane-3- 594 carboxylate cd (S)-ethy 1 8-(2-amino-6-((R)- 1 -(4-
(4-ethoxy-4-oxobutyl)-2-(3- methyl- 1 H-pyrazol- 1 -yl)phenyl)-
A 674
252,2-trifluoroethoxy)pyi'imidin-4- yl)-2,8-diazaspiiO[4.5]decane-3- carboxylate
ce (S)-ethyl 8-(2-amino-6-((R)-l-(3'- cyano-3-(3 -methyl- 1 H-pyrazol- 1 -
N yl)-[lfl'-biphenyl]-4-yl)-2,2,2-
A trifluoroethoxy)pyrimidin-4-yl)- 661
2,8-diazaspii [4.5]decane-3- carboxylate
cf (S)-ethyl 8-(2-amino-6-((R)- 1 -(5- chloro-3'-cyano-[l ,1 '-biphenyl]-2- yl)-2,2,2-
B 615 trifluoi ethoxy)pyrimidin-4-yl)-
2,8-diazaspiiO[4.5]decane-3- carboxylate
Figure imgf000287_0001
cn (S)-ethyl 8-(2-amino-6-((R)-2,252- trifiuoro- 1 -(4'-isopropoxy-3 -(3- methyl- lH-pyrazol- 1 -yl)-[ 1,1 '-
A biphenyl]-4-yl)ethoxy)pyrimidin- 694 4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate co (S)-ethyl 8-(2-amino-6-((R>2,2,2- iiifluoi -l-(4-(quinoxalin-6-
A yl)phenyl)ethoxy)pyrimidin-4-yl)- 608
2,8-diazaspiio[4.5]decane-3- carboxylate
cp (S)-ethyl 8-(6-((R)-l-(4'-
(acetamidomethyl)-3-(3-methyl-
N lH-pyrazol-1 -yl)-[l , 1 -biphenyl]-
4-yl)-252,2-tiifluoroethoxy)-2-
A 707 aminopyrimidin-4-yl)-2,8- diazaspiro[4,5]decane-3- carboxylate
0
cq (S)-ethyl 8-(6-((R)- l-(4'-(2- acetamidoethyl)-3-(3-methyl-l H- pyrazol-1 -yl)-[l , 1 '-biphenyl]-4-
A yl)-2;2,2-ti'ifluoiOethoxy)-2- 721
H aminopynmidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
cr (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro- 1 -(2-(3 -methyl- 1 H- pyrazol-l-yl)-4-(qumolin-7-
A 687 yl)phenyl)ethoxy)pyrimidin-4-yl)- 2, 8-diazaspiro [ .5]decane-3 - carboxylate
cs (S)-ethyl 8-(2-amino-6-((R)-252,2- irifluoro-l-(4-(2-methoxypyridin-
N 4-yl)-2-(3-methy 1- 1 H-pyrazol - 1 -
A yl)phenyl)ethoxy)pyrimidin-4-yl)- 666
2,8-diazaspiro[4.5]decane-3- carboxylate
ct (S)-ethyl 8-(6-((R l-(4-(lH- indol-6-yl)-2-(3-methyl-lH- pyrazol- 1 -yl)phenyl)-2,2,2-
A 595 trifluoroetlioxy)-2- aminopyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-
Figure imgf000289_0001
Figure imgf000290_0001
Figure imgf000291_0001
dn (S)-ethyl 8~(6-((R)-l-(4-
(acetamidomethyl)-2-(3-methyI-
N 1 H-pyrazol- 1 -y l)pheny 1) -2,2 ,2-
A ti-ifluoroethoxy)-2- 631 aminopyi'imidin-4-yl)-2,8- diazaspiro[4.5]decane-3- o carboxylate
do (3S)-ethyl 8-(2-amino-6-((lR)- 2,2,2-trifluoro - 1 -(3 -(3 -methyl- 1 H- pyrazol-l~yl)-4'-((2-((2-
0 oxotetrahydrofuran-3-
A 823 yl)thio)ethyl)carbamoyl)-[ 1 , 1 '- biphenyl]-4-yl)ethoxy)pyrimidin- 4-yi)-2,8-diazaspiiO[4.5]decane-3- carboxylate
dp (S)-ethyl 8-(2-amino-6-((R)-l ~
(3,4-dimethyl-3"-
(methylsulfonyl)-[l!l,:3',l"-
A terphenyl]-4'-yl)-2,2,2- 738 trifluoroethoxy)pyrimidin-4-yl)-
2,8-diazaspiro[4.5]decane-3- carboxylate
dq (S)-ethyl 8-(2-amino-6-((R)~2,2,2- triiluoro- 1 -(3'-(methylsulfonyl)-5- (quinolin-6-yl)- [ 1 , 1 '-biphenyl] -2-
A 761 yl) ethoxy)pyri mi di n-4-y 1) -2, 8 -
0=S=:O diazaspiro [4.5 ]decane -3 -
1 carboxylate
dr HO (S)-ethyl 8-(2-amino-6-((R)-2,2,2- trifluoro- 1 -(4'-(hydroxymethyl)-3'- methyl-4-(3-methyl- lH-pyrazo - 1 -
A yl)-[l,l'-biphenyl]-3- 680 yl)ethoxy)pyrirnidin-4-yl)-2,8- di azaspiro [4.5 ] decane -3- caiboxylate
ds HO (S)-ethyl 8-(2-amino~6-((R)-2,2,2- trifluoro- 1 -(3'-(hydi'Oxymethyl)-4'- methyl-4-(3 -methyl- 1 H-pyrazol- 1 -
A yl)-[U'-biphenyl]-3- 680 yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3- carboxylate
Figure imgf000293_0001
F carboxylate
Figure imgf000294_0001
eg (S)-ethyl 8-(2-amino-6-((R)-2,2,2-
X s ~ trifluoro- 1 -(2-(3-methyl- 1H- pyrazoI-l-yl)-5-(pyrimidin-5-
A 638 yl)plienyl)ethoxy)pyrimidin~4-yl)- 2, 8- diazasph o [4.5] decane-3 - carboxylate
eh (S)-ethyl 8-(2-amino-6-((R)-l-
(4,,5-dichloiO-3'-fluoiO-[l,r- biphenyI]-2-yl)-2,2,2-
B 643 trifluoiOethoxy)pynmidin-4~yl)-
2,8-diazaspiro[4.5]decane-3-
^^^^ carboxylate
ei (S)-ethyl 8-(2-amino-6-((R)- 1 -(5- chloiO-3'-ethoxy-[l, -biphenyl]- 2-yl)-2,2,2-
B 635 trifluoi'oethoxy)pyrimidiii-4-yl)-
2,8-diazaspiiO[4.5]decane-3-
CI carboxylate
ej CI (S)-ethyl 8-(2-amino-6-((R)- l -
(3, }5-dichloi -4'-ethoxy-[l)r- biphenyl]-2-yl)-2,2,2-
B 669 trifluoiOethoxy)pyrimidiii-4-yl)-
2, 8-diazaspho[4 ,5]decane-3 -
CI carboxylate
ek CI (S)-ethyl 8-(2-amino-6-((R)- l -
(S'^-dichloro-S'-fluoro-tl ,!'- biphenyl]-2-yl)-2;2,2-
B 643 trifluoiOethoxy)pyrimidin-4-yl)-
2,8-diazaspiro[4.5]decane-3-
CI carboxylate
el (S)-ethyl 8-(2-amino-6-((R)- 1 -(3'- (tert-butyl)-5-chloro-[l,r- biphenyl]-2-yl)-2t2,2-
B trifliwroethoxy)pyrin"tidin-4-yl)- 647 258-diazaspiro[4.5]decane-3-
CI carboxylate
em CI (S)-ethyl 8-(2-amino-6-((R)-l-
(31 , 5 -dichloro -5 '-(trifluoromethyl) -
[l,l,-biphenyl]-2-yl)-2>2,2-
B 693 trifluoiOethoxy)pyrimidin-4-yl)-
2,8-diazaspiio[4.5]decane-3-
CI carboxylate en (S)-ethyl 8-(2-amino-6-((R)- 1 -(5-
F
chloi -3'-fluoiO-5'- (trifluoromethyl)-[l , 1 '-biphenyl]-
B 2-yl)-2,2,2- 677 trifluoiOethoxy)pynmidin-4-yl)-
Cl 2,8-diazaspiro[4.5]decane-3- carboxylate
eo ct (S)-ethyl 8-(2-amino-6-((R)- 1 -(3'- chloro-[l , 1 '-biphenyl]-2-yl)-2,2,2-
B trifluoroethoxy)pyrimidin-4-yl)- 591 258-diazaspiro[4.5]decane-3- carboxylate
ep (S)-ethyl 8-(2-amino-6-((R)-l-(5- chloro-3'-niethoxy-[l ,1 '-biphenyl]- 2-yl)-2,2,2-
B 621 trifluoroethoxy)pyrimidin-4-yl)-
2,8-diazaspiro[4.5]decane-3- carboxylate
eq (S)-ethyl 8-(2-amino-6-((R)-l -(5- chIoro-3'-isopropoxy-[1 , V- biphenyl] -2-yl) -2,2,2-
B trifluoroethoxy)pyrimidin-4-yl)- 649 2,8-diazaspiro[4.5]decane-3- carboxylate
Cl
er ct (S)-ethyl 8-(2-amino-6-((R)-l -
(3',5-dichloiO-4t-methyl-[l , 1 '- biplienyl]-2-yl)-2,2,2-
B 639 trifluoiOethoxy)pyrimidin-4-yl)-
2,8-diazaspiro[4.5]decane-3-
Cl carboxyiate
es Cl (S)-ethyl 8-(2-amino-6-((R)-l- (3',5-dichloiO-4'-isopiOpoxy-[l ,1 '- biphenyl]-2-yi)-2,2,2-
B 683 trifluoroethoxy)pyrimidin-4-yl)- 2,8-diazasph'o [4.5]decane-3 -
Cl carboxylate
et F (S)-ethyl 8-(2-amino-6-((R)-l-(5- chloro-3'-fluoro-4'-isopropoxy-
[l,l '-biphenyl]-2-yl)-2,2,2-
B 667 trifluoiOethoxy)pyrimidin-4-yl)-
2,8-diazaspiro[4.5]decane-3-
Cl carboxylate eu (S)-ethyl 8-(2-amino-6-((R)-l-
(4'}5-dichloro-3'-(trifluoromethyl)-
[l ,l'-bipnenyl]-2-yl)-2,2,2-
B 693 trifluoroethoxy)pyrimidin-4-yl)-
2,8-diazaspii'o[4,5]decane-3- carboxylate
ev F (S)-ethyl 8-(2-amino-6-((R)-l -(5- ch loro-3 ' -fluoio - [ 1 , Γ -bipheny 1] -2- yl)-2,2,2-
B 609 trifluoiOethoxy)pynmidin-4-yl)-
2,8-diazaspiro[4.5]decane-3-
CI carboxylate
ew (S)-ethyl 8-(2-amino-6-((R)-l-
(4',5-dichloiO-3'-methyl-[ 1 , 1
biphenyl]-2-yl)-2,2,2-
B 639 trifluoi ethoxy)pyrimidin-4-yl)-
2,8-diazaspiro[4.5]decane-3- carboxylate
ex (S)-ethyl 8-(2-amino-6-((R)-l-
(3',5-dichloiO-4'-(trifluoromethyl)-
[ '- i heny^-yl)^^-
B 693 trifluoroethoxy)pyrimidin-4-yl)-
2,8-diazaspiro [4.5]decane-3 -
CI carboxylate
ey F (S)-ethyl 8-(2-amino-6-((R)-l-(5-
Figure imgf000297_0001
biphenyI]-2-yl)-2,2,2-
B
trifluoroethoxy)pyrimidm-4-yl)-
2,8-diazaspiro[4.5]decane-3-
CI carboxylate
ez CI (S)-ethyl 8-(2-amino-6-((R)-l-
(3'55-dic loiO-4,-fluoro-[ 1,1'- biphenyl]-2-yl)-2,2,2-
B
trifluoroethoxy)pyrimidin-4-yl)-
2,8-diazaspii-o[4.5]decane-3-
CI carboxylate
fa F (S)-ethyl 8-(2-amino-6-((R)-l-(5-
Figure imgf000297_0002
biphenyl]-2-yl)-2,2,2-
B
trifiuoroethoxy)pyri midin- 4- y 1)-
2,8-diazaspiro[4.5]decane-3-
CI carboxylate fb (S)-ethyl 8-(2-amino-6-((R)-l-(5- chloiO-3VV-dimethyl-[l,l'- biphenyl]-2-yl)-2,2,2-
B 619 trifluoiOethoxy)pyrimidin-4-yl)-
2,8-diazaspii'o[4.5]decane-3- carboxylate
fc (S)-ethyl 8-(2-amh o-6-((R)-l- (4,,5-dichloiO-3',5,-dimethyl-[l ,1'- bi phenyl] -2-yl) -2,2 ,2-
B 653 tfifluoro ethoxy)pyrim id in-4 -y 1) - 2,8-diazaspiro[4.5]decane-3- carboxy ate
fd F (S)-ethy 1 8-(2-ammo~6-((R)- 1 -(5- chloro-4'-ethoxy-3 '-fluoro-[l , 1 '- biphenyl]-2-yl)-2,2,2-
B 653 trifluoroethoxy)pyrimidin-4-yl)-
2,8-diazaspiiO[4.5]decane-3-
CI carboxylate
fe (S)-ethyl 8~(2-amino-6-((R)-l-(5- chloro-S'^'-dimethyHU*- biphenyl]-2-yl)"2;2,2-
B 619 trifluoi ethoxy)pyrimidin-4-yl)-
2,8-diazaspiro[4.5]decane-3- carboxylate
ff CI (S)-ethyl 8-(2-amino-6-((R)-l-
(3'}5-dichloi -5'-methyl-[l, l '- biphenyl]-2-yl)-2,2,2-
B 639 trifluoiOethoxy)pyrimidin-4-yl)-
2}8-diazaspiro[4.5]decane-3-
CI carboxylate
fg (S)-ethyl 8-(2-amino-6-((R)-l -(5- chloiO-4'-fluoi -3,-methyl-[l , 1
biphenyl]-2-yl)-2,2,2-
623 trifluoroethoxy)pyrimidin-4-yl)-
2,8-diazaspiro[4.5]decane-3- carboxylate
fli (S)-ethyl 8-(2-amino-6-((R)- 1 -(5- chloro-3'-metliyl-4'-
(trifluoromethoxy)-[l , 1 '-
B biphenyl] -2-yl)-2,2,2- 689 trifluoiOethoxy)pynmidin-4-yl)-
CI 2,8-diazaspiro[4.5]decane-3- carboxylate fi (S)-ethyl 8-(2-amino-6-((R)-l -(5- chloro-3 '-(trifluoromethoxy)- [ 1 , - biphenyl]-2-yl)-2,2,2-
B trifluoiOethoxy)pyi'imidin-4-yl)- 675
2,8-diazaspiro[4.5]decane-3- carboxylate
Ci
fj (S)-ethyl 8-(2-amino-6-((R> 1 -(5- chloro-3'-isopropyl-[l , 1 '- biphenyl]-2-yl)-2,2,2-
B 633 tri fIuoroethoxy)pynmidi n- 4-y 1) -
2,8-diazaspiro[4.5]decane-3- carboxylate
fk F (S)-ethyl 8-(2-amino-6-((R)-l-(5-
F-4-F chloro -3 ' , 5 '-bis(trifluoromethyl) -
[l,l'-biphenyl]-2-yI)-2,2J2-
B trifluoiOethoxy)pyrimidin-4-yl)- 727
2}8-diazaspiro[4.5]decane-3- carboxylate
CI
fl F (S)-ethyl 8-(2-amino-6-((R)-l-(5- chloro-3'-fluoro-4'-methyl-[l , 1 '- biphenyl]-2-yl)-2,2,2-
B 623 trifluoroethoxy)pyrimidin-4-yl)-
2,8-diazaspiro[4.5]decane-3-
CS carboxylate
fm (S)-ethyl 8-(2-amino-6-((R>2,2,2- trifluoro- 1 -(3',5,5'-tnchloro-[l ,1
B biphenyl]-2-yl)ethoxy)pyi'imidin- 659 4-yl)-2,8-diazaspiiO[4,5]decane-3- carboxylate
Figure imgf000299_0001
fn F (S)-ethyl 8-(2-amino-6-((R)- 1-(5- chloiO-4,-fluoro-3'- (trifluoromethyl)-[l , 1 '-biphenyl]-
B 2-yl)-2,2,2- 677 trifluoroethoxy)pyrimidin-4-yl)-
2,8-diazaspiiO[4.5]decane-3-
CI cavboxylate
fo (S)-ethyl 8-(2-amino-6-((R)-l-(4- chloiO-2-(pyridin-3-yl)pheny])-
B 2,2,2-trifluoiOethoxy)pyrimidin-4- 592 yl)-2,8-diazaspiro[4.5]decane-3-
C! carboxylate
Figure imgf000300_0001
carboxylate
Figure imgf000301_0001
Figure imgf000302_0001
carboxylate
Figure imgf000303_0001
carboxylate
Figure imgf000304_0001
Figure imgf000305_0001
carboxylate
Figure imgf000306_0001
Figure imgf000307_0001
hm (S)-ethyl 8-(2-amino-6-((R)-l-(4- chloro-2-(naphthalen-2- yl)phenyl)-2,2,2-
B trifliioroethoxy)pyrimidin-4-yl)- 641
2 , 8 -diazaspiro [4.5 ]decane-3 - carboxylate
hn (S)-ethyl 8-(2-amino-6-((R)-l -(3'-
(tert-butyl)-5-chloro-[ 1 , 1 '- biphenyl]-2-yl)-2)2,2-
B 647 tt'ifI\ioroetlioxy)pyiimidin-4-yl)-
2,8-diazaspiro[4.5]decane-3- carboxylate
ho (S)-ethyl 8-(6-((R)-l-(2-(lH- benzo[d]imidazol- 1 -yl)-4- chlorophenyl)-2,2)2-
B trifluoroethoxy)-2- 631 aminopy rim idi n- 4-yl) -2,8- diazaspiro[4.5]decane-3- carboxylate
hp (S)-ethyl 8-(2-amino-6-((R)- 1 -(4- chloro-2-(lH-indazol-l - yl)phenyl)-2,2,2-
B 631 trifluoi ethoxy)pyrimidin-4-yl)- 2, 8 -diazaspi ro [4 , 5] decane- 3 - carboxylate
hq (S)-ethyl 8-(2-amino-6-((R)- 1 -(4- chloro -2-(2 -i sopropylpyridi n- 4- yl)phenyl)-2,2,2-
B tri fluoro ethoxy)py rimidin-4 -y 1)- 634
2,8 -diazaspiro [4.5]decane-3 - carboxylate hr (S)-ethyl 8-(2-amino-6-(( )-l-(5- chloi -4'-fluoi -[l j -biphenyl]-2- yl)-2,2,2-
B trifluoroethoxy)pyr i m idi n-4 -y 1) - 609
2,8-diazaspiro[4.5]decane-3- carboxylate
F
hs (S)-ethyl 8-(2-amino~6-((R)-l-
(4,,5-dichloi -[l,l '-biphenyl]-2- yl)-2,2,2-
B 625 trifluoi ethoxy)pyiimidin-4-yl)-
2,8-diazaspiro[4.5]decane-3- carboxylate
Figure imgf000309_0001
carboxylate
Figure imgf000310_0001
Figure imgf000311_0001
Figure imgf000312_0001
Figure imgf000313_0001
Figure imgf000314_0001
Figure imgf000315_0001
Figure imgf000316_0001
Figure imgf000317_0001
carboxylate
Figure imgf000318_0001
Figure imgf000319_0001
carboxylate kp HO (S)-ethyl 8-(2-ammo-6-((R)-252,2- trifluoro-l-(3,-(hydiOxymethyl)-4'- methyl-3 -(3 -methyl- 1 H-pyrazol- 1 -
A yl)-[l,l'-biphenyl]-4- 681 yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspko[4.5]decane-3- carboxylate
kq (S)-ethyl 8-(2~amino-6-((R)-2;2,2- trifluoro- 1 -(4'-(hydiOxymethyl)-3'- methyl-3-(3-methy 1- H-pyrazol- 1 -
A yl)-[lJl,-biplienyl]-4- 681 yl)ethoxy)pyrimidin-4-yI)-2,8- diazaspi io [4.5] decaiie-3 -
Figure imgf000320_0001
carboxylate
kr (S)-ethyl 8-(2-amino-6-((R)- 1 -(4-
(6-ethoxypyridin-3-yl)-2-(3- methyl- 1 H-pyrazol- 1 -yl)phenyl)-
A 2t2,2-trifluoroethoxy)pyrimidin-4- 681 yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
ks (S)-ethyi 8-(2-amino-6-((R)-2,2,2-
O N. / trifluoro- 1 -(4-(6-methoxypyridm- 3-yi)-2-(3 -methyl- 1 H-pyrazol- 1 -
A 668 yl)phenyl) ethoxy)pyiimidin~4 -yl)- 2,8-diazaspiro[4.5]decane-3- carboxylate
kt (S)-ethyl 8-(2-arnino-6-((R)-l-(5~
chloro-3'-(2-methoxyethoxy)-
[l;r-biphenyl]-2-yl)-2,2,2- 665 trifluoroethoxy)pyrimidin-4-yl)-
A 2,8-diazaspiro[4.5]decane-3- carboxylate ku (S)-ethyl 8-(2-amino-6-((R)- 1 -(4- chloro-2-(pyrazin-2-yl)phenyl)-
B 2 ,2,2-trifluoiOethoxy)pyri m id in- 4- 594 yl)-2,8-diazaspiro[4.5]decane-3- carboxylate 3kv (S)-ethyl 8-(2-amino-6-((S)- l-
(3',4'-bis(hydiOxymethyl)-3-(3- met yl- 1 H-pyrazol- 1 -y 1) - [ 1 , -
B biphenyl]-4-yl)-2,2,2- 697 trifluoiOethoxy)pyrimidin-4-yl)-
2,8-diazaspiro[4,5]decane-3-
Figure imgf000321_0001
carboxylate
Table 18b.
NMR Data for Compounds of Table 18a
Figure imgf000321_0002
J = 10.7 Hz, 1H), 3.00 (d, J = 10.6 Hz, 1H), 3.52 (dt, J = 1 1.4, 5.4 Hz, 7H), 3.96 (t, J = 7.8 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 4.61 (s, 2H), 5.54 (s, 1H), 6.64 (q, J = 7.1 Hz, 1H), 7.66 (q, J = 8.4 Hz, 5H), 8.12 (t, J = 4.2 Hz, 2H), 8.94 (s, 1H)
g Ή NMR (400 MHz, MeOH-d4): δ ppm 1.32 (m, 4H), 1.64 (dq, J - 14.1, 8.9, 7.2 Hz, 4H), 2.03 (td, J = 13.3, 8.9 Hz, 1H), 2.49 (dd, J = 13.6, 8.7 Hz, 1H), 3.27 (s, 2H), 3.58 (m, 4H), 3.88 (d, J = 1 1.8 Hz, 6H), 4.32 (qd, J = 7.2, 2.5 Hz, 2H), 4.58 (t, J = 8.8 Hz, 1H), 6.62 (q, J = 7.1 Hz, 1H), 7.03 (m, 1H), 7.19 (m, 2H), 7.57 (d, J - 8.2 Hz, 2H), 7.64 (m, 2H)
h 'H NMR (400 MHz, CDC13): δ ppm 7.769-7.796 (m,lH), 7.707-7.740(m,2H), 7.585- 7.636(m, 4H), 7.422-7.444(m, 1H), 6.738-6.762(m,lH), 6.579-6.658-6.537 (m, 1H),5.521 (s, 1H), 4.612 (s,2H), 4.200-4.253 (q,2H), 4.114-4.154 (t, 1H), 3.747(s,3H), 3.475-3.523 (m, 4H), 3.047-3.160 (m,2H), 2.171-2.726 (m, 1H), 1.840-1.891 (m, 1H), 1.543-1.649 (m, 4H), 1.209-1.305 (t, 3H)
i Ή NMR (400 MHz, DMSO-d6): δ ppm 1.25 (t, J=7.10 Hz, 3 H) 1.42 - 1.69 (m, 4 H) 1.92 (dd, J=13.25, 9,35 Hz, 1 H) 2.35 (dd, J=13.25, 8,47 Hz, 1 H) 3, 14 (br. s., 2 H) 3.60 (br. s., 4 H) 4.24 (qd, J=7.09, 2.10 Hz, 2 H) 4.54 (br, s, 1 H) 5.77 (br, s., 1 H) 6.70 (q, J=6.65 Hz, 1 H) 7.37 (d, J=2.10 Hz, 1 H) 7.43 - 7.52 (m, 3 H) 7.53 - 7.69 (m, 4 H) 9.23 (br. s., 1 H) 10.44 (br. s., 1 H)
j !H NMR (400 MHz, CD30D): δ ppm 7.66-7.64 (d, 1 H, J=8.6 Hz), 7.43-7.41 (d, 1 H, J=8.6 Hz), 7,26-7.20 (m, 2 H), 6.82-6.68 (m, 4 H), 5.42 (s, 1 H), 4.19-4, 16 (q, 1 H, J=7.0 Hz), 3.83-3.81 (t, 1 H), 3.49-3.47 (m, 4 H), 2,91-2.89 (d, 1 H, J=10.9 Hz), 2.77- 2.75 (d, 1 H, J=10.9 Hz), 2.1 1-2.07 (m, 1 H), 2.12-2.10 (m, 1 H), 1.53-1.51 (m, 4 H), 1.28-1.25 (t, 3 H, J=7.0 Hz Hz)
k Ή NMR (400 MHz, MeOH-d4): δ ppm 8.42 (s, 1 H), 8.30 (d, 1 H), 7.61 (m, 2 H), 7.31 (m, 1 H), 7.10 (s, 1 H), 6.58 (m, 1 H), 5,57 (s, 1 H), 4.20 (m, 2 H), 3.84 (m, 1 H), 3.48 (m, 4 H),3.16 (s, 3 H), 2.77 (m, 1 H), 2,70 (m, 1 H), 2.61 (m, 1 H),2.14 (m, 1 H), 1.77 (m, 1 H), 1.65 (m, 2 H), 1.54 (m, 4 H), 1.20 (m, 3 H), 0.98 (m, 3 H)
1 Ή NMR (400 MHz, CD30D-d4): δ ppm 1.28-1.24 (m, 4 H), 7.72-7.68 (m, 3 H), 1.52 (m, 4 H), 1.71 (m, 1 H), 2.10 (m, 1 H), 2.32 (s, 3 H), 2.76-2.73 (m, 1 H), 2.90-2.87 (m, 1 H), 3.49 (m, 4 H), 3.75 (s, 3 H), 3.81 (m, 2 H), 4.20-4.15 (m, 2 H), 5.54(s. lH), 6.65- 6.59 (m, 1 H), 6.93 (s, 1 H), 7.37-7.34(m, 1 H), 7.45-7.42 (m, 1 H), 7.57-7.55 (m, 2 H)m !H NMR (400 MHz, MeOH-d4): δ ppm 8.19 (s, 1 H), 7.64 (d, 1 H), 7.53-7.42 (m, 5 H), 7.29 (s, 1 H), 7.16 (s, 2 H), 6.63 (q, 1 H), 6.52-6.35 (m, 3 H), 5,80-5.77 (d, 1 H), 5.50 (s, 1 H), 4.21-4.18 (m, 2 H), 3.97 (t, 1 H), 3.49 (m, 4 H), 2.98-2.95 (d, 1 H), 2.86- 2.83 (d, 1 H), 2.16-2.14 (m, 1 H), 1.80-1.76 (m, 1 H), 1.54 (m, 4 H), 1.19-1.16 (t, 3 H)n Ή NMR (400 MHz, MeOH-d4): δ ppm 1.27 (q, J = 7.1 , 6.1 Hz, 4H), 1.52 (dt, J = 10.4, 5.7 Hz, 4H), 1.74 (dd, J = 13.0, 7.2 Hz, 1H), 2.09 (dd, J = 13.1 , 8.8 Hz, 1H), 2.75 (d, J = 1 1.0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 3.52 (tq, J = 14.5, 8.2 Hz, 4H), 3.82 (dd, J = 8.8, 7,2 Hz, 1H), 3.90 (s, 3H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 4.89 (d, J = 1.5 Hz, 13H), 5.51 (d, J = 18.8 Hz, 2H), 6.62 (q, J = 7.1 Hz, 1H), 7.15 (t, J = 8.6 Hz, 1H), 7,39 (m, 2H), 7.59 (m, 4H)
o 'H-NMR (400 MHz, MeOH-d4): δ ppm 68.00(d,J=2.36 Ηζ,ΙΗ) ,7.88(dd, J=2.6,6.76 Ηζ,ΙΗ), 7.58(m,4H),6.62(m, 2H),5.55(s, lH),4.22(m,3H) ,3.64(s,3H),3.52(m, 4H),3.02(m, 2H),2.27(m;lH),1.89(m, lH),1.59(m,4H),1.29(t, J=7.16 Hz,3H).
p !H NMR (400 MHz, MeOH-d4): δ ppm 7,62(d,2H,J=8.0), 7.56(d,2H,J=8.0),
7,45(m,2H), 6.93(d,lH,J=8.0), 6.62 (q, 1H,J=8.0), 5.54 (s, 1H), 4.21 (t, 2H, J=4.0),3.99 (t, IH, J=4.0), 3.5653.49 (m, 4H), 3.00(dd, 3H,J=20.0,8.0), 2.86 (d, IH, J = 8.0),2.59-2.57 (m, 2H), 2.18 (dd, 2H, J = 12.0,8.0), 1.80(dd, 2H, J = 8.0,4.0), 1.54(m, 5),l ,28(t, 4H, J = 8.0)
q Ή-NMR (400 MHz, CDC13): δ ppm 1 1.76 (m,lH) ,7.84 -7.86 (m,lH) ,7.70 -7.73 (m,2H),7.59 (m, 4H),7.43 -7.45 (m, 1H),6.73 -6.75 (m,lH), 6.57 -6.63 (q, IH), 5.53 (s, 1I-I), 4.61 (s,2H) , 4.17 -4.23 (q,2H), 3.90 -3.94 (t, IH), 3.48 -3.51 (m, 4H), 2.86 - 2.99 (m,2H); 2.07-2.12 (m, 2H), 1.74 -1.79 (m, IH), 1.53 -1.59 (m, 4H),1.24 -1.29 (t, 3H).
r ¾ NMR (400 MHz, CD30D-d4): 5 ppm 8.42 (s, 1 H), 8.04 (d, 1 H), 7.79 (m, 3 H), 7.63 (m, 1 H), 7.46 (m, 1 H), 6.58 (m, 1 H), 6.40 (m, 1 H), 5.56 (m, 1 H), 4.18 (m, 2 H), 3.83 (m, 1 H), 3.50 (m, 4 H), 3.21(s, 3 H), 2.90 (m, 1 H), 2.78 (m, 1 H),2.14 (m, 1 H), 1.86 (m; 3 H), 1.76(m, 1 H), 1.54 (m, 4 H), 1.26 (m, 3 H)
s ¾ NMR (MeOH-d4): 5 ppm 0.90 (t, J = 6.9 Hz, IH), 1.17 (p, J = 6.3 Hz, 3H), 1.29 (s, 2H), 1.56 (m, 4H), 1.80 (s, IH), 2.29 (s, IH), 2.41 (s, 3H), 2.80 (m, 4H), 3.26 (d, J = 1 1.3 Hz, IH), 3.44 (s, H), 4.09 (tdd, J = 14.2, 7.9, 4.6 Hz, 2H), 4.48 (s, IH), 4.87 (s, 2H), 5.56 (s, IH), 6.42 (t, J = 2.2 Hz, IH), 6.93 (m, IH), 7.46 (m, 4H), 7.61 (m, 2H), 7.80 (dd, J = 8.3, 2.2 Hz, IH), 7.93 (dd, J = 5.2, 2.5 Hz, 2H)
t JH NMR (MeOH-d4): δ ppm 0.91 (dd, J = 12.4, 6.3 Hz, 2H), 1.17 (q, J = 7.4 Hz, 3H), 1.31 (d, J = 16.3 Hz, 3H), 1.65 (m, 4H), 1.83 (s, IH), 2.32 (s, 2H), 2.41 (s, 3H), 2.92 (ddt, J = 18.2, 14.3, 9.1 Hz, 5H), 3.28 (s, IH), 4.11 (dtt, J - 10.7, 7.1, 3.9 Hz, 2H), 4.48 (s, IH), 4.95 (d, J = 1 1.7 Hz, IH), 6.43 (d, J = 2.2 Hz, IH), 6.94 (q, J = 6.5 Hz, IH), 7.50 (m, 3H), 7.61 (dd, J = 8.6, 2.1 Hz, 2H), 7.79 (dt, J = 8.3, 1.4 Hz, IH), 7.93 (dd, J = 10.2, 3.2 Hz, 2H)
u ]H NMR (400 MHz, CDCl3-d) ; 5 ppm 8.50 (s, IH), 7.99-7.96 (m, IH), 7.69-7.63 (m, 2H), 7.51 (s, IH), 7.25-7.23 (m, IH), 7.11 (d, J = 7.8 Hz, IH), 6.57 (q, J - 6.6 Hz, IH), 5.51 (s, IH), 5.18 (s, 2H), 4.21 (q, J = 7.1 Hz, 2H), 3.93-3.89 (m, IH), 3.53-3.48 (m, 4H), 3.14 (s, 3H), 2.93 (dd, Jl = 10.6 Hz, J2 = 42.0 Hz, 2H), 2.66-2.62 (m, 2H), 2.12-2.07 (m, IH), 1.79-1.74 (m, IH), 1.69-1.63 (m, 2H), 1.61-1.58 (m, 2H)} 1.55- 1.52 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H), 0.95 (t, J = 7,3 Hz, 3H)
v 'H NMR (400 MHz, CDC13): δ ppm 8,52 (d, J = 9.5 Hz, IH), 7.99-7.97 (m, IH), 7.69-7.62 (m, 3H), 7.38 (dd, Jl = 7.9 Hz, J2 = 20.6 Hz, IH), 7.15 (dd, Jl = 7.9 Hz, J2 = 17,0 Hz, IH), 6.57 (m, IH), 6,46-6,42 (m, IH), 6.34-5,84 (m, IH), 5.51-5.50 (m, IH), 5.18 (s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 3.87 (t, J = 7,6 Hz, IH), 3.52-3.50 (m, 4H), 3.15-3.14 (m, 3H), 2.90 (dd, Jl = 10.2 Hz, J2 = 47.8 Hz, 2H), 2.10-2.05 (m, IH), 1.91 (d, J = 6.4 Hz, 3H), 1.78- 1.73 (m, IH), 1.58- .53 (m, 4H), 1.28 (t, J = 7.1 Hz, 3H)w 'H NMR (400 MHz, MeOH-d4): δ ppm 8.49 (s, IH), 7.98 (d, J = 7,5 Hz, IH), 7.71 (t, J = 7.8 Hz, IH), 7.65-7.63 (m, 2H), 7.42-7.40 (m, IH), 7.23 (d, J = 1.9 Hz, IH), 6.53 (q, J = 6.8 Hz, IH), 5.48 (s, IH), 5.26 (s, 2H), 4.22 (q, J = 7.1 Hz, 2H), 4,03 (t, J = 8.0 Hz, IH), 3.52-3.51 (m, 4H), 3.21 (q, J = 7.4 Hz, 2H), 3.02 (dd, Jl = 10.9 Hz, J2 = 34.9 Hz, 2H), 2.18-2.12 (m, IH), 1.85-1.80 (m, IH), 1.62-1.61 (m, 2H), 1.56-1.55 (m, 2H), 1.31-1.28 (m, 6H)
x IH NMR (400 MHz, MeOH-d4): δ ppm 8.45 (s, lH),8.03(d,lH,J=8.0),
7.83(t,lH,J=8.0), 7,79-7.69(m,2H),7.50(d,lH,J=8.0), 7.37(s,lH), 6,62 (q, 1H,J=8.0), 5.61 (s, IH), 4,38 (t, lH,J=8.0),4.32-4.27 (m, 2H), 3.64-3.49(m, 4H),3.16(q,
2H,J=12.0), 2.39 (dd, IH, J = 12.0,8.0), 1.98 (dd, IH, J = 12.0,8.0), 1.70-1.62(m, 7H),1.31(dd, 5H, J = 12.0,8.0) 0.96(t, 4H,J=8.0) y Ή NMR (400 MHz, MeOH-d4): δ ppm 8.50 (s, 1 H), 8.05-8.03 (d, 1 H), 7.82 (t, 1 H), 7.76-7.70 (m, 2 H), 7.52-7.51 (d, 1 H), 7.38-7.37 (d, 1 H), 6.62-6.60 (q, 1 H), 5.60 (s, 1 H), 4.20-4.19 (q, 2 H), 3.85 (t, 1 H), 3.57 (m, 4 H), 2.82 (d, 1 H), 2.77 (d, 1 H), 2.09 (m, 1 H), 1.77 (m, 1 H), 1.57 (m, 6 H), 1.31 (q, 2 H), 1.26 (m, 3 H), 0.84-0.81 (t, 3 H)
z Ή NMR (400 MHz, MeOH-d4): δ ppm 0.09 (dd, J = 4.2, 2.0 Hz, IH), 0.90 (t, J = 6.5 Hz, 3H), 1.28 (m, 14H), 1.54 (dt, J = 10.5, 5.6 Hz, 6H), 1.76 (dd, J = 13.2, 7.3 Hz, IH), 2.03 (s, IH), 2.15 (ddd, J - 29.1, 14.1, 8.4 Hz, 2H), 2.78 (d, J = 10.9 Hz, IH), 2.92 (d, J = 1 1.0 Hz, IH), 3.53 (td, J = 13.8, 13.4, 6.0 Hz, 6H), 3.86 (dd, J = 8.8, 7.3 Hz, IH), 4.20 (m, 3H), 5.46 (d, J = 22.4 Hz, 3H), 5.56 (s, IH), 6.67 (q, J = 7.2 Hz, 2H), 7.66 (d, J = 8.1 Hz, 3H), 7.75 (in, 3H), 7.85 (m, 3H), 7.93 (d, J = 7.9 Hz, 2H)aa Ή NMR (400 MHz, MeOH-d4): δ ppm: 8.16 (d,J = 8.84 Ηζ,ΙΗ), 8.03 (d,J =1.84 Hz, lH),7.94-7.81(m,2H), 7.77 (d,J - 8.32 Hz,2H), 7.64(d,J = 8.24 Hz,2H), 6.96 (d,J - 8.88 Ηζ,ΙΗ), 6.65 (q, J = 7.08 Ηζ,ΙΗ), 5.56 (s,lH), 4.18 (m,2H), 4,06(s,3H), 3.82 (m, IH), 3.53(m, 4H), 2.90 (d, J=11.0 Ηζ,ΙΗ), 2.76 (d, J=11.0 Ηζ,ΙΗ), 2.09 (m, IH), 1.75(m, IH), 1 ,53 (s, 4H),1.27 (t, J = 7.12 Hz,3H)
ab Ή NMR (400 MHz, CDC13): δ ppm 7.76 (s, IH), 7,65 (d, J = 8.5 Hz, IH), 7.43 (t, J = 7.6 Hz, IH), 7.37 (dd, Jl = 2.2 Hz, J2 = 8.5 Hz, IH), 7.33 (d, J = 7.6 Hz, IH), 7.28 (d, J = 7.8 Hz, IH), 7.24 (d, J = 2.2 Hz, IH), 6.63 (q, J = 6.7 Hz, IH), 5.41 (s, IH), 5.02 (s, 2H), 4.80 (m, 2H), 4.21 (q, J = 7.1 Hz, 2H), 4.05-4.01 (m, IH), 3.48-3.46 (m, 4H), 3.01 (dd, Jl = 10.9 Hz, J2 = 31.0 Hz, 2H), 2.17-2.1 1 (m, IH), 1.83-1.78 (m, IH), 1.59-1.50 (m, 4H), 1.28 (t, J = 7.1 Hz, 3H)
ac 'H-NMR (400 MHz, MeOH-d4): δ ppm 7.97 (s,lH) ,7.60 -7,67 (m,2H), 7.52 -7.56 (m,lH),7.43 -7.45 (m, 1H),7.31 -7.31 (m, 1H),7,22 -7.24 (m,lH),6.621-6.663(m, lH),5.498(s, IH), 4.16 -4.22 (m, 2H), 4.92-4.03 (m, 2H), 3.83 -3.87 (M, lh), 3,46 - 3,53 (m,4H), 2.90 -2.92 (d,lH), 2.76 -2.78 (d,lH), 2.59 -2.63 (m, 2H), 2.10 -2.22 (m, 3H), 1.71 -1.78 (m, 1H),1.52 -1.55 (m, 4H), 1.25 -1.28 (m, 3H)
ad 1 H-NMR (400 MHz, MeOH-d4) δ ppm: 7.98 (s,lH) , 7.63 -7.65 (m,lH), 7.42 -7.50 (m,3H), 7.30 -7.30 (m, IH), 7.05 -7.07 (m, IH), 6.62-6.67 (m,lH), 5.49 (s, IH), 4.15 - 4.22 (m, 2H), 3.80 -3.98 (m, 3H), 3.46 -3.56 (m, 6h), 2.73-2.92 (m,4H), 2.73 -2.78 (d,lH), 2.07 -2, 13 (d,lH), 1.73 -1.78 (m, IH), 1.49 -1.57 (m, 4H), 1.25 -1.29 (m, 3H)ae Ή NMR (400 MHz, DMSO-d6) δ ppm: 1.25 (t, J=7.10 Hz, 3 H) 1.42 - 1.69 (m, 4 H) 1.92 (dd, J=13.25, 9.35 Hz, 1 H) 2.35 (dd, J= 13.25, 8.47 Hz, 1 H) 3.14 (br. s., 2 H) 3.60 (br. s., 4 H) 4.24 (qd, J=7.09, 2.10 Hz, 2 H) 4.54 (br. s., 1 H) 5,77 (br. s„ 1 H) 6.70 (q, J=6.65 Hz, 1 H) 7.37 (d, J=2.10 Hz, 1 H) 7.43 - 7.52 (m, 3 H) 7.53 - 7.69 (m, 4 H) 9.23 (br. s., 1 H) 10.44 (br. s., 1 H)
af Ή NMR (400 MHz, MeOH-d4): δ ppm 7.66 (d, 1 H,J=8.4 Hz ), 7.50 (m, 3 H), 7.31 (d, 2 H,J=8.7 Hz), 7,24 (d, 1 H,J=7.2 Hz), 6.64 (m, 1 H), 5.50 (m, 1 H), 4.21 (m, 1 H), 3.87 (m, 1 H), 3.53 (m, 4 H), 3.01(s, 3 H), 3.18 (m, 1 H), 2.90 (m, 3 H), 2.79 (m, 1 H),2.07 (m, 1 H), 1.74 (m, 1 H), 1.53 (m, 4 H), 1.27 (m, 3 H)
ag Ή NMR (400 MHz, CDC13): δ ppm 7.54 (d, J = 2.2 Hz, IH), 7.51 (d, J = 8.6 Hz, IH), 7.19 (dd, Jl = 2.6 Hz, J2 = 8.6 Hz, IH), 6.85 (q, J = 6.6 Hz, IH), 5,49 (s, IH), 4.56 (s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 3.90-3.86 (m, IH), 3.53-3.47 (m, 4H), 2.90 (dd, Jl = 10.4 Hz, J2 = 47.6 Hz, 2H), 2.13-2.05 (m, IH), 1.78-1.73 (m, IH), 1.59-1.56 (m, 2H), 1.54-1.51 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H)
ah Ή NMR (400 MHz, CDC13): δ ppm 7.54 (d, J = 2.2 Hz, IH), 7.51 (d, J = 8.6 Hz, IH), 7.19 (dd, Ji = 2.6 Hz, J2 = 8.6 Hz, IH), 6.85 (q, J = 6.6 Hz, IH), 5,49 (s, I H), 4.56 (s, 2H), 4,20 (q, J = 7,2 Hz, 2H), 3.90-3.86 (m, IH), 3.53-3.47 (m, 4H)5 2.90 (dd, Jl - 10.4 Hz, J2 = 47.6 Hz, 2H), 2.13-2.05 (m3 IH), 1.78-1.73 (m, IH), 1.59-1.56 (m, 2H), 1.54-1.51 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H)
ai Ή NMR (400 MHz, MeOH-d4): δ ppm 8.06 (d, J = 8.72 Ηζ,ΙΗ), 8.01 (s, 1H),7.94 (s ,2H),7.76 (d, J = 8,28 Hz, 2H),7.64 (d, J = 8.16 Hz, 2H), 7.31 (d, J = 8.68 Hz, IH), 6.66 (q, J = 7.32 Hz, IH), 5.56 (s, IH), 4, 18 (q, J = 7.04 Hz, 2H), 3.84-3.80 (m, IH), 3.51 (m, 4H), 2.89 (d, J = 10.96 Hz, IH), 2.75 (d,J = 1 1 Ηζ,ΙΗ), 2.68(s, 3H), 2.10- 2.01 (m, IH), 1.76-1.71 (m, IH), 1.54-1.49 (m, 4H), 1.25 (t, J = 7.12 Hz, 3H)aj Ή NMR (400 MHz, MeOH-d4): δ ppm 7.69 (d, J = 1.8 Ηζ,ΙΗ), 7.60-7.57 (d, IH), 7,48 (dd, Jl =2,44, J2=8.6 Hz, IH), 6.96 (q, J = 7.32 Hz, IH), 5.56 (s, IH), 4.19 (q, J = 7.12 Hz, 2H), 3.86-3.82 (m, IH), 3.54 (m, 4H), 2.91 (d, J = 11 Hz, IH), 2.77 (d,J = 1 1 Ηζ,ίΗ), 2.14-2.08(m,l H), 1.79-1 ,73 (m, IH), 1.55 (m, 4H), 1.27 (t, J = 7.12 Hz, 3H)
ak Ή NMR (400 MHz, MeOH-d4): 8 ppm 7.91 (s, IH), 7.71 (dd, Jl= 6.12 Hz,J2= 1.96 Hz,lH),7.63 (m,2H), 7.56-7.49 (m,7H),7.39-7.35 (m,2H), 6.74 (q, J = 6.88 Hz, IH), 5.50(s, IH), 4.18 (q, J = 6.96 Hz, 2H), 3.83 (m, IH), 3.50 (m, 4H), 2.89 (d, J = 11.04 Hz, IH), 2.75 (d,J = 11 Ηζ,ΙΗ), 2.12-2.06 (m,lH), 1.76-1.71 (m, IH), 1.54-1.49 (m, 4H), 1.27 (t, J = 7.12 Hz, 3H)
al Ή NMR (400 MHz, MeOH-d4): 6 ppm 0.84 (t, J = 7.1 Hz, 8H), 1.26 (t, J = 7.1 Hz, 8H), 1.50 (dt, J = 1 1 ,1 , 5.8 Hz, 4H), 1.73 (dd, J = 13.1 , 7.1 Hz, IH), 2,06 (dd, J = 13.1, 8.8 Hz, IH), 2.38 (s, 3H), 2.73 (d, J = 1 1.0 Hz, IH), 2.88 (d, J = 1 1.0 Hz, IH), 3.51 (m, 4H), 3.81 (dd, J = 8.7, 7.1 Hz, IH), 4.00 (qd, J = 7.1, 4.5 Hz, 2H), 4.17 (qd, J = 7.1, 1 ,5 Hz, 2H), 5.74 (s, IH), 6.39 (d, J = 2.3 Hz, IH), 6.85 (q, J = 6.7 Hz, IH), 7.45 (m, 5H), 7.80 (m, 2H), 7.90 (d, J = 2.4 Hz, IH)
am Ή NMR (400 MHz, MeOH-d4): δ ppm 0.89 (m, IH), 1.26 (m, 7H), 1.40 (t, J = 7.1 Hz, 3H), 1.51 (m, 4H), 1.73 (dd, J = 13.1, 7.2 Hz, IH), 2.05 (m, IH), 2,40 (s, 3H), 2.74 (d, J = 1 1.0 Hz, 1 H), 2,88 (d, J = 11.0 Hz, IH), 3.53 (in, 4H), 3.81 (dd, J = 8.8, 7.1 Hz, IH), 4, 18 (qd, J = 7.1, 2.5 Hz, 2H), 4.39 (q, J = 7.1 Hz, 2H), 5.73 (s, IH), 6.43 (d, J = 2.4 Hz, IH), 6.82 (q, J = 6.6 Hz, IH), 7.57 (t, J = 7.8 Hz, IH), 7.68 (d, J = 1.9 Hz, IH), 7.79 (m, 2H), 7.90 (dt, J = 8.0, 1.4 Hz, IH), 8.02 (m, 2H), 8.28 (d, J = 1.9 Hz, IH)
an ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.33 (dt, J = 54.3, 7.1 Hz, 6H), 1.50 (dt, J = 10.8, 5.8 Hz, 4H), 1.73 (dd, J = 13.1, 7.2 Hz, IH), 2.07 (dd, J = 13.1 , 8.8 Hz, IH), 2.40 (s, 3H), 2.74 (d, J = 11.0 Hz, IH), 2.88 (d, J = 11.0 Hz, IH), 3.52 (m, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, IH), 4.18 (qd, J = 7.1, 1 ,5 Hz, 2H), 4.38 (q, J = 7.1 Hz, 2H), 5.74 (s, IH), 6.43 (d, J = 2.3 Hz, IH), 6.84 (q, J = 6.6 Hz, IH), 7.77 (m, 5H), 8.00 (d, J = 2.3 Hz, IH), 8.09 (m, 2H)
ao !H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz, 3H), 1.54 (m, 4H), 1.76 (dd, J = 13.1 , 7.2 Hz, IH), 2.11 (dd, J = 13.1, 8.7 Hz, IH), 2.77 (dd, J = 11.0, 1.1 Hz, IH), 2.91 (d, J = 11,0 Hz, IH), 3.53 (td, J = 1 1.9, 11.4, 4.9 Hz, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, IH), 4.19 (qd, J = 7.2, 1.6 Hz, 2H), 5.53 (s, IH), 7.15 (t, J = 8.0 Hz, IH), 7.27 (q, J = 8.0 Hz, H), 7.69 (m, 2H)
ap ¾ NMR (400 MHz, CDC13): δ ppm 1.28 (m, 4H), 1.56 (dq, J = 25.2, 5.5, 4.9 Hz, 4H), 1.78 (dd, J = 13.1 , 6.9 Hz, H), 2.12 (m, IH), 2.90 (d, J = 10.7 Hz, IH), 2.99 (d, J = 10.6 Hz, IH), 3.49 (dt, J = 11 ,5, 5.7 Hz, 4H), 3.94 (dd, J = 8.8, 6.9 Hz, IH), 4.21 (q, J = 7.1 Hz, 2H), 4.58 (s, 2H), 5.43 (s, 1H), 6.55 (q, J = 6.8 Hz, 1H), 7.24 (m, 3H), 7.41 (m, 3H), 7.65 (m, 2H)
aq Ή NMR (400 MHz, CDC13): δ ppm 0.84 (m, 2H), 1.14 (s, 1H), 1.28 (t, J = 7.1 Hz, 3H), 1.53 (m, 4H)} 1.74 (dd, J = 13.1, 6.8 Hz, 1H), 2.05 (m, 1H), 2.43 (s, 3H), 2.82 (d, J = 10.5 Hz, 1H), 2.94 (d, J -10.5 Hz, 1H), 3.46 (dt, J = 14.0, 5.8 Hz, 4H), 3.86 (dd, J = 8.8, 6.7 Hz, IH), 4.19 (q, J = 7.1 Hz, 2H), 4.35 (s, 2H), 5.40 (s, 1H), 6.61 (q, J = 6.8 Hz, IH), 7.33 (m, 5H), 7.65 (d, J = 8.5 Hz, IH)
ar ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz, 4H), 1.54 (dt, J = 7.9, 4.7 Hz, 4H), 1.76 (dd, J = 13.1, 7.2 Hz, IH), 2.12 (m, IH), 2.78 (m, IH), 2.90 (m, IH), 3.52 (m, 4H), 3.85 (td, J = 9.2, 8.8, 7.3 Hz, IH), 4.19 (qd, J = 7.1, 1.6 Hz, 2H), 4.86 (d, J = 0.8 Hz, 1 IH), 5.51 (d, J = 13,8 Hz, IH), 6.52 (q, J = 6.7 Hz, IH), 7.34 (d, J = 2.2 Hz, IH), 7,51 (dd, J = 8.5, 2.2 Hz, IH), 7.75 (m,5H)
as Ή NMR (400 MHz, MeOH-d4): δ ppm 1.32 (t, J = 7.1 Hz, 3H), 1.67 (m, 4H), 2.05 (dd, J = 13.6, 8.8 Hz, IH), 2.46 (d, J = 45.5 Hz, 7H), 2.66 (s, IH), 3.28 (s, 211), 3.69 (m, 4H), 4.32 (qd, J = 7.1, 2.3 Hz, 2H), 4.58 (t, J = 8.7 Hz, IH), 6.43 (d, J = 2.4 Hz, IH), 6.85 (q, J = 6.3 Hz, IH), 7.37 (m, 2H), 7.66 (m, 3H), 7.79 (m, 2H), 7.97 (d, J = 2.4 Hz, IH)
at lH NMR ( eOH-d4): δ ppm 1.28 (m, 15H), 1.53 (m, 13H), 1 ,76 (dd, J = 13.1 , 7,3 Hz, 3H), 1.86 (s, IH), 2.12 (dd, J = 13.1, 8.8 Hz, 3H), 2.79 (d, J = 11.0 Hz, 3H), 2.92 (d, J = 1 1.0 Hz, 3H), 3.51 (qdt, J = 18.0, 13.3, 5.9 Hz, 12H), 3.63 (d, J = 8.6 Hz, IH), 3.87 (m, 3H), 4.19 (qd, J = 7.1 , 1.6 Hz, 5H), 5.51 (s, 3H), 6.68 (q, J = 6.7 Hz, 3H), 7.29 (m, 6H), 7.47 (m, 19H), 7.65 (m, 5H)
au ¾ NMR (MeOH-d4): δ ppm 1.13 (s, 2H), 1.26 (t, J - 7.3 Hz, 4H), 1.49 (m, 6H), 1.73 (dd, J = 13.1, 7.2 Hz, IH), 2.06 (dd, J = 13.1 , 8.7 Hz, IH), 2.38 (d, J = 12.1 Hz, 7H),
2.73 (d, J = 11.0 Hz, IH), 2.87 (d, J = 11.0 Hz, IH), 3.53 (tt, J = 14.1, 5.1 Hz, 5H), 3.81 (m, IH), 4.18 (tt, J = 7.8, 3.6 Hz, 2H), 4.81 (s, 2H), 4.97 (d, J = 15.9 Hz, IH),
5.74 (s, 1H), 6.41 (d, J = 2.1 Hz, IH), 6.78 (q, J = 6,7 Hz, IH), 7,26 (d, J = 7.9 Hz, 2H), 7.57 (m, 5H), 7.73 (m, 2H), 7.96 (d, J = 2.3 Hz, IH)
av >H NMR (MeOH-d4): δ ppm 1.26 (m, 3H), 1.51 (dt, J - 10.6, 5.6 Hz, 4H), 1.74 (dd, J = 13.1 , 7.2 Hz, IH), 2.07 (dd, J = 13.1, 8.8 Hz, IH), 2,40 (s, 7H), 2.74 (d, J = 10.9 Hz, IH), 2.88 (d, J = 1 1.0 Hz, I H), 3.54 (m, 4H), 3.81 (dd, J = 8.8, 7.1 Hz, IH), 4, 18 (qd, J = 7.1, 1.6 Hz, 2H), 5.74 (s, IH), 6.42 (d, J = 2.4 Hz, IH), 6.79 (q, J = 6.6 Hz, IH), 7.21 (d, J = 7.5 Hz, IH), 7.33 (t, J = 7.6 Hz, IH), 7.46 (m, 2H), 7.62 (d, J - 1 ,9 Hz, IH), 7.75 (m, 2H), 7.98 (d, J = 2.4 Hz, IH)
aw ¾ NMR (MeOH~d4): δ ppm 0.90 (m, IH), 1.27 (m, 5H), 1 ,51 (dt, J = 10.5, 5.6 Hz, 4H), 1.75 (dd, J = 13.1 , 7.2 Hz, IH), 2.09 (dd, J = 13.1 , 8.7 Hz, IH), 2.40 (s, 3H), 2.76 (d, J = 1 1.0 Hz, IH), 2.90 (d, J = 11.0 Hz, IH), 3.54 (m, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, IH), 4.19 (qd, J - 7.1, 1.7 Hz, 2H), 5.73 (s, IH), 6.43 (d, J = 2.4 Hz, IH), 6.84 (q, J = 6.5 Hz, IH), 7.64 (m, 3H), 7.80 (m, 3H), 8.01 (d, J = 2.4 Hz, IH)
ax 'H NMR (400 MHz, Chloroform-d): δ ppm 1.27 (m, 9H), 1 ,52 (dt, J = 22.3, 5.4 Hz, 4H), 1.72 (d, J = 13.1 Hz, IH), 2.05 (m, IH), 2.25 (ddd, J = 18.1, 13.9, 8.2 Hz, 2H), 2.63 (m, 2H), 2.82 (d, J - 10.5 Hz, IH), 2.94 (d, J = 10.4 Hz, IH), 3.48 (dd, J = 13.6, 7.4 Hz, 5H), 3.63 (m, IH), 3.81 (m, 4H), 4.19 (q, J = 7.1 Hz, 2H), 4.86 (s, 2H), 5,46 (s, IH), 6.46 (m, IH), 7,22 (d, J = 2.2 Hz, IH), 7.34 (dd, J = 8.5, 2.2 Hz, IH), 7.59 (d, J = 8.5 Hz, IH)
ay ¾ NMR (400 MHz, MeOH-d4): δ ppm 1 ,35 (d, J=2.64 Hz, 4 H) 1.61 - 1 ,86 (m, 5 H) 2.04 - 2.16 (m, 1 H) 2.42 (d, J=1.27 Hz, 3 H) 2.48 - 2.60 (m, 1 H) 3.55 - 4.03 (m, 4 H) 4.25 - 4.44 (m, 2 H) 4.55 - 4.70 (m, 1 H) 6.45 (s, 1 H) 6.90 - 7.04 (m, 1 H) 7.61 (s, 2 H) 7.68 - 7.79 (m, 1 H) 7.88 - 8.00 (m, 1 H)
az ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.25 (t, J=7.15 Hz, 3 H) 1.43 - 1.60 (m, 4 H) 1.78 (dd, J=13.13, 7.42 Hz, 1 H) 2.13 (dd, J=13.08, 8.74 Hz, 1 H) 2.35 (s, 3 H) 2.73 - 3.01 (m, 2 H) 3.39 - 3.63 (m, 4 H) 3.94 (t, J=7.91 Hz, 1 H) 4.18 (qd, J=7.13, 1.78 Hz, 2 H) 5.65 (s, 1 H) 6.38 (d,J=2.39 Hz, 1 H) 6.79 (q, J=6.74 Hz, 1 H) 7.41 - 7.54 (m, 2 H) 7.68 (d, J=8.35 Hz, 1 H) 7.91 (d, J=2.34 Hz, 1 H)
ba 'H MR (400 MHz, MeOH-d4): δ ppm 1.33 (t, J = 7.13 Hz, 3 H), 1.53 - 1.75 (m, 4 H), 2.05 (dd, J = 13.62, 8.88 Hz, 1 H), 2.49 (dd, J = 13.57, 8.74 Hz, 1 H), 3.27 (s, 2 H), 3.42 - 3.74 (m, 4 H), 3.84(s, 3 H), 4.25 - 4.40 (m, 2 H), 4.58 (t, J = 8.79 Hz, 1 H), 5.60 (s, 1 H), 6.59 - 6.71 (m, 1 H), 6.92 (ddd, J = 8.22, 2.54, 0.76 Hz, 1 H), 7.11 - 7.16 (m, 1 H), 7.16 - 7.24 (m, 1 H), 7.31 - 7.38 (m, 1 H), 7.54 - 7.61 (m, 2 H), 7.62 - 7.70 (m, 2 H)
bb Ή NMR (400 MHz, dichloromethane-d2): δ ppm 1.29 (t, J=7.15 Hz, 3 H) 1.47 - 1.85 (m, 4 H) 2.01 (dd, J=13.52, 8.30 Hz, 1 H) 2.30 - 2.36(m, 1 H) 2.38 (s, 3 H) 3.27 - 3.41 (m, 2 H) 3.41 - 3.67 (m, 4 H) 3.82 (s, 3 H) 4.26 (qd, J=7.17, 4.00 Hz, 2 H) 4.45 (t, J=8,49 Hz, 1 H) 4.96 (br. s, 2H) 5.49 (s, 1 H) 6.31 (d, J=2.25 Hz, 1 H) 6.62 (q, J=6.90 Hz, 1 H) 6.88 (d, J=2.59 Hz, 1 H) 6.96 (dd, J=8.81, 2.61 Hz, 1 H) 7.61 (d, J=8,74 Hz, 1 H) 7.66 (d, J=2.25 Hz, 1 H)
bc !H NMR (400 MHz, MeOH-d4): δ ppm 1.35 (t, J-7.22 Hz, 3 H) 1.67 - 1.89 (m, 4 H) 2.05 - 2.18 ( , 1 H) 2.49 - 2.62 (m, 1 H) 3.56 - 3.90 (m, 4 H) 4.35 (dd, J=7.13, 1.85 Hz, 2 H) 4,65 (s, 1 H) 5.97 (s,l H) 6.58 - 6.72 (m, 1 H) 7.14 (br. s„ 1 H) 7.41 (d, J=9.18 Hz, 1 H) 7,45 - 7.53 (m, 2 H) 7,64 - 7.72 (m, 2 H) 7.73 - 7.82 (m, 2 H)bd 'H NMR (400 MHz, MeOH-d4): δ ppm 1.28 - 1.39 (m, 4 H) 1 ,74 (d, J=18.35 Hz, 4 H) 2.03 - 2.14 (m, 1 H) 2.35 (d, J=12.89 Hz, 6 H) 2.43 (s, 3 H) 2.46 - 2.57 (m, 1 H) 3.62 - 3.96 (m, 4 H) 4.34 (dd, JM7.13, 1.85 Hz, 2 H) 4.56 - 4.68 (m, 1 H) 6.44 (d, J=2.34 Hz, 1 H) 6.50 - 6.61 (m, 1 H) 6.81 - 6.96 (m, 1 H) 7.26 (d, J=7.81 Hz, 1 H) 7.40 - 7.47 (m, 1 H) 7.50 (s, 1 H) 7.68 (d, J=l .37 Hz, 1 H) 7.78 (s, 1 H) 7.82 (d, J=l .37 Hz, 1 H) 7.98; (d, J=2.15 Hz, 1 H)
be !H NMR (400 MHz, MeOH-d4): δ ppm 1.30 (m, 6 H) 1.59 (m, 4 H) 2.02 (m, 1 H) 2.38 (s, 3 H) 2.45 (dd, J=13.54, 8.76 Hz, 1 H) 2.72 (q, J=7.60 Hz, 2 H) 3.24 (m, 2 H) 3.58 (m, 4 H) 4.32 (m, 2 H) 4.53 (t,J=8.76 Hz, 1 H) 5.72 (s, 1 H) 6.38 (d, J=2.20 Hz, 1 H) 6.71 (m, 1 H) 7.25 (d, J=1.56 Hz, 1 H) 7.36 (dd, J=8.10, 1.61 Hz, 1 H) 7.63 (d, J=8.10 Hz, 1 H) 7.85 (d, J=2.29 Hz, 1 H)
bf Ή NMR (400 MHz, MeOH-d4): δ ppm 0.96 (t, J=7.35 Hz, 2 H) 1.32 (t, J=7.15 Hz, 4 H) 1.63 (m, 6 H) 2.00 (dd, J=13.59, 8.61 Hz, 1 H) 2.37 (s, 3 H) 2.42 (m, 1 H) 2.66 (m, 2 H) 3.21 (m, 2 H) 3.58 (m, 4 H) 4.31 (m, 2 H) 4.49 (t, J=8.69 Hz, 1 H) 5.72 (s, 1 H) 6.38 (d, J=2.29 Hz, i H) 6.71 (q, J=6.67 Hz, 1 H) 7.23 (d, J=1.66 Hz, 1 H) 7.34 (dd, J=8.10, 1.66 Hz, 1 H) 7.63 (d, J=8.10 Hz, 1 H) 7.85 (d, J=2.
29 Hz, 1 H)
bg !H NMR (400 MHz, MeOH-d4): δ ppm 0.95 (t, J=7.35 Hz, 3 H) 1.32 (t, J=7.15 Hz, 4 H) 1.63 (m, 6 H) 2.02 (m, 1 H) 2.38 (s, 3 H) 2.45 (dd, J=13.54, 8.76 Hz, 1 H) 2.69 (m, 2 H) 3.24 (m, 2 H) 3.58 (m, 4 H) 4.32 (m, 2 H) 4.53 (t, J=8.74 Hz, 1 H) 5.72 (s, 1 H) 6.38 (d, J-2.29 Hz, 1 H) 6.71
(m, 1 H) 7.23 (d, J=1.61 Hz, 1 H) 7,34 (dd, J=8.15, 1.61 Hz, 1 H) 7.62 (d, J=8.15 Hz, 1 H) 7.85 (d, J=2.34 Hz, 1 H)
bh 'H NMR (400 MHz, CHLOROFORM-d) : δ ppm 1.18-1.36 (m, 3 H) 1.43 (t, J =6.74 Hz, 3 H) 1.54-2.29 (m, 6 H) 2.39 (br. s., 3 H) 3.78 (br. s„ 4 H) 4.26 (br. s„ 2 H) 4.42 (d J =6.15 Hz, 2 H) 5.53 (br. s„ 1 H) 6.36 (s, 1 H) 6.59 (br. s., 1 H) 7.48 (d, J =7.96 Hz, 1 H)7.61(br. s., 1 H) 8.16 (d, J=8.05Hz, 1 H) 8.34 (br. s., 1 H)
bi Ή NMR (400 MHz, MeOH-d4): δ ppm 1.24 - 1.30 (m, 5 H) 1.37 (t, J=7.13 Hz, 3 H) 1.45 - 1.62 (m, 4 H) 1.84 (dd, J=13.32, 7.86 Hz, 1 H) 1.95 (s, 4 H) 2.22 (dd, J=13.30, 8.86 Hz, 1 H) 2.38 (s, 3 H) 2.88 - 3.09 (m, 2 H) 3.41 - 3.71 (m, 4 H) 4.10 (t, J=8.25 Hz, 1 H) 4.22 (qd, J=7.13, 2.00 Hz, 2 H) 4.37 (q, J=7.13 Hz, 2 H) 5.66 (s, 1 H) 6.41 (d, J=2.39 Hz, 1 H) 6.84 (q, J=6.54 Hz, 1 H) 7.83 (d, J=8.30 Hz, 1 H) 7.94 (d, J=2.34 Hz, 1 H) 7.99 (d, J=1.61 Hz, 1 H) 8.08 (dd, J=8.27, 1.64 Hz, 1 H)
bj 'H NMR (400 MHz, MeOH-d4): δ ppm 1.31 (td, J=7.13, 3.22 Hz, 6 H) 1.52 - 1.64 (m, 4 H) 1.97 (s, 1 H) 2.01 (dd, 3.59, 8.81 Hz, 1 H) 2.37 (s, 3 H) 2.44 (dd, J=13.62, 8.74 Hz, 1 H) 3.18 - 3.26 (m, 2 H) 3.43 - 3.68 (m, 4 H) 4.19 - 4.34 (m, 4 H) 4.53 (t, J=8.74 Hz, 1 H) 5.75 (s, 1 H) 6.40 (d, J=2.39 Hz, 1 H) 6.55 (d, J=16.06 Hz, 1 H) 6.95 (q, J=6.56 Hz, 1 H) 7.46 (d, J=8.30Hz, 1 H) 7.68 (d, J=16.06 Hz, 1 H) 7.80 (dd, J=8.32, 2.03 Hz, 1 H) 7.87 (s, 1 H) 7.91 (d, J=2.39 Hz, 1 H)
bk Ή NMR (400 MHz, MeOH-d4): δ ppm 0.92 (t, J=7.37 Hz, 3 H) 1.32 (dq, J=14.94, 7.38 Hz, 2 H) 1.50 - 1.68 (m, 6 H) 2.06 (dd, J=13.37, 7.22 Hz, 1 H) 2.31 (dd, J=13.45, 9.25 Hz, 1 H) 2.37 (s, 3 H) 2.69 (t, J=7.59 Hz, 2 H) 3.06 - 3.29 (m, 2 H) 3.41 - 3.76 (m, 4 H) 4.08 (dd, J=9.20, 7.25 Hz, 1 H) 5.75 (s, 1 H) 6.36 (d, J=2.15 Hz, 1 H) 6.69 (q, J=6.62 Hz, 1 H) 7.28 - 7.33 (m, 1 H) 7.34 - 7.39 (m, 1 H) 7.53 (s, 1 H) 7.82 (d, J=2.29 Hz, 1 H)
bl Ή NMR (400 MHz, DMSO-d6): δ ppm 1.50 - 1.73 (m, 4 H) 1.80 (quin, J=7,52 Hz, 2 H) 1.90 (dd, J=13.23, 9.22 Hz, 1 H) 2.15 - 2.26 (m, 2 H) 2.27 - 2.41 (m, 4 H) 2.69 (t, J=7.66 Hz, 2 H) 3.00 - 3.20 (m, 2 H) 3.69 (br. s., 4 H) 4.33 - 4.52 (m, 1 H) 6.14 (br. s., 1 H) 6.38 (d, J=2.29 Hz, 1 H) 7.05 (br. s„ 1 H) 7.37 - 7.52 (m, 3 H) 7.76 (br. s., 1 H) 8.02 (d, J=2.29 Hz, 1 H) 8.97 (d, J=5.32 Hz, 1 H) 10.42 (br. s., 1 H)
bm 'H NMR (400 MHz, MeOH-d4): δ ppm 1.31 (t, J=7.15 Hz, 3 H) 1.52 - 1.70 (m, 4 H) 1.90 (dd, J=6.30, 1.22 Hz, 3 H) 1 ,97 (dd, J=13.52, 8.44 Hz, 1 H) 2,35 - 2.41 (m, 4 H) 3.06 - 3.24 (m, 2 H) 3.42 - 3.79 (m, 4 H) 4.21 - 4.35 (m, 2 H) 4.40 (t, J=8.57 Hz, 1 H) 5.75 (s, 1 H) 6.27 - 6.54 (m, 3 H) 6.75 (q, J=6.64 Hz, 1 H) 7.32 (d, J=8.25 Hz, 1 H) 7.52 (dd, J=8.30, 2.00 Hz, 1 H) 7.64 (s, 1 H) 7.83 (d, J=2.29 Hz, 1 H)
bn ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.32 (t, J=7.15 Hz, 3 H) .49 - 1.70 (m, 4 H) 2.01 (dd, J= 13.59, 8.76 Hz, 1 H) 2.29 (s, 3 H) 2.32 (s, 3 H) 2.40 (s, 3 H) 2.40 - 2.44 (m, 1 H) 3.24 (s, 2 H) 3.43 - 3.71 (m, 4 H) 4.22 - 4.41 (m, 2 H) 4.56 (t, J=8.74 Hz, 1 H) 5.80 (s, 1 H) 6.41 (d, J=2.29 Hz, 1 H) 6.81 - 6.92 (m, 1 H) 7.20 (d, J=7.81 Hz, 1 H) 7.26 - 7.32 (m, 1 H) 7.35 (s, 1 H) 7.45 (d, J=8.30 Hz, 1 H) 7.73 (dd, J=8,27, 2.12 Hz, 1 H) 7.88 - 7.90 (m, 2 H)
bo ¾ NMR (400 MHz, MeOH-d4): δ ppm 0.92 (t, J=7.35 Hz, 3 H) 1.32 (t, J=7.13 Hz, 3 H) 1.49 - 1.76 (m, 6 H) 1.94 - 2.06 (m, 1 H) 2.37 (s, 3 H) 2.43 (dd, J=13.57, 8.79 Hz,
1 H) 2.66 (t, J=7.52 Hz, 2 H)3.13 - 3.28 (m, 2 H) 3.43 - 3.76 (m, 4 H) 4,21 - 4.39 (m,
2 H) 4.50 (t, J=8.66 Hz, 1 H) 5.74 (s, 1 H) 6.37 (d, J=2.29 Hz, 1 H) 6.70 (q, J=6.69 Hz, 1 H) 7.26 - 7.33 (m, 1 H) 7.34 - 7.42 (m, 1 H) 7.53 (s, 1 H) 7.82 (d, J=2.29 Hz, 1 H)
bp Ή NMR (400 MHz, MeOH-d4): δ ppm 1.25 (t, J=7.61 Hz, 3 H) 1.33 (t, J=7.15 Hz, 3 H) 1.57 - 1.71 (m, 4 H) 2.04 (dd, J=13.93, 8.52 Hz, 1 H) 2.37 (s, 3 H) 2.47 (dd, J=13.62, 8.74 Hz, 1 H) 2.72 (q, J=7.61 Hz, 2 H) 3.26 (d, J=1.51 Hz, 2 H) 3.44 - 3.77 (m, 4 H) 4.23 - 4.43 (m, 2 H) 4.57 (t, J=8.79 Hz, 1 H) 5.76 (s, 1 H) 6.37 (d, J=2,20 Hz, 1 H) 6.63 - 6.78 (m, 3 H) 7.27 - 7.35 (m, 1 H) 7.36 - 7.46 (m, 1 H) 7.55 (s, 1 H) 7.81 (d, J-2.29 Hz, 1 H)
bq Ή NMR (400 MHz, MeOH-d4): δ ppm 0.92 (t, J=7.35 Hz, 3 H) 1.22 - 1.42 (m, 5 H) 1.49 - 1.75 (m, 6 H) 1.94 - 2.08 (m, 1 H) 2.37 (s, 3 H) 2.44 (dd, J=13.57, 8.74 Hz, 1 H) 2.68 (t, J=7.61 Hz, 2 H) 3.15 - 3.29 (m, 2 H) 3,42 - 3.76 (m, 4 H) 4.23 - 4.40 (m, 2 H) 4.53 (t, J=8.74 Hz, 1 H) 5,75 (s, 1 H) 6.37 (d, J=2.34 Hz, 1 H) 6.70 (q, J=6.69 Hz, 1 H) 7.27 - 7,33 (m, 1 H) 7.34 - 7.41 (m, 1 H) 7.53 (s, 1 H) 7.82 (d, J=2.34 Hz, 1 H)br 'H NMR (400 MHz, MeOH-d4): 8 ppm 1.33 (t, J=7.13 Hz, 3 H) 1.53 - 1.74 (m, 4 H) 2.05 (dd, J=13.62, 8.83 Hz, 1 H) 2.38 (s, 3 H) 2.48 (dd, J=13.62, 8.79 Hz, 1 H) 3.28 (s, 2 H) 3.44 - 3.79 (m, 4 H) 4.22 - 4.43 (m, 2 H) 4.59 (t, J=8.79 Hz, 1 H) 5.37 (d, J=l 1.08 Hz, 1 H) 5.73 - 5.96 (m, 2 H) 6.39 (d, J=2.34 Hz, 1 H) 6.68 - 6.95 (m, 2 H) 7.40 (d, J=8.25 Hz, 1 H) 7.65 (dd, J=8,27, 1.98 Hz, 1 H) 7.73 (s, 1 H) 7.87 (d, J=2.34 Hz, 1 H)
bs Ή NMR (400 MHz, MeOH-d4): δ ppm 1.11 (t, J=7.47 Hz, 3 H) 1.33 (t, J=7.15 Hz, 3 H) 1.51 - 1.72 (m, 4 H) 2.04 (dd, J=13.62, 8.83 Hz, 1 H) 2.18 - 2.33 (m, 2 H) 2.38 (s, 3 H) 2.47 (dd, J=13.59, 8.81 Hz, 1 H) 3.26 (s, 2 H) 3.44 - 3.78 (m, 4 H) 4.19 - 4.43 (m, 2 H) 4.58 (t, J=8.79 Hz, 1 H) 5.79 (s, 1 H) 6.30 - 6.53 (m, 3 H) 6.69 - 6.84 (m, 1 H) 7.33 (d, J=8.25 Hz, 1 H) 7.55 (dd, J=8.30, 2,00 Hz, 1 H) 7,65 (s, 1 H) 7.84 (d, J=2.34 Hz, 1 H)
bt ¾ NMR (400 MHz, MeOH-d4); δ ppm 1.30 (t, J=7.13 Hz, 3 H) 1.45 - 1.65 (m, 4 H) 1.79 - 1.91 (m, 1 H) 2.16 - 2.32 (m, 1 H) 3.03 (s, 2 H) 3.51 (br. s., 4 H) 3.75 - 3,81 (m, 1 H) 4.07 - 4.17 (m, 1 H) 4.20 - 4,32 (m, 2 H) 5.55 (s, 1 H) 6.65 (d, J=2.34 Hz, 1 H) 7.15 - 7.28 (m, 1 H) 7.36 - 7.46 (m, 1 H) 7.57 (d, J=2.15 Hz, 1 H) 7,62 - 7.70 (m, 1 H) 7,73 (d, J=2.15 Hz, 1 H)
b ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.29 (t, J=7.13 Hz, 3 H) 1.40 - 1.61 (m, 4 H) 1.71 - 1.86 (m, 1 H) 2.07 - 2.22 (m, 1 H) 2.86 (s, 1 H) 2.94 (s, 1 H) 3.50 (d, J=4,69 Hz, 4 H) 4.00 (s, 4 H) 4.22 (dd, J=7,22, 0.98 Hz, 2 H) 5.57 (s, 1 H) 6.61 (d, J=2.15 Hz, 1 H) 7.13 - 7.28 (m, 1 H) 7.35 - 7.50 (m, 2 H) 7.55 (d, J=1.17 Hz, 1 H) 7.72 (d, J=2.34 Hz, 2 H)
bv Ή NMR (400 MHz, MeOH-d4): δ ppm 1.35 (t, J=7.13 Hz, 3 H) 1.57 - 1.83 (m, 4 H) 1.99 - 2.16 (m, 1 H) 2.56 (s, 4 H) 3.31 (s, 2 H) 3.68 (br, s., 4 H) 4.03 (s, 3 H) 4.35 (dd, J=7.03, 2.15 Hz, 2 H) 4.62 (s, 1 H) 5.70 (s, 1 H) 6.70 (d, J=6.83 Hz, 1 H) 7.42 (dd, J=8.49, 0.88 Hz, 1 H) 7.60 - 7.72 (m, 3 H) 7.73 - 7.86 (m, 3 H)
bw Ή NMR (400 MHz, MeOH-d4): δ ppm 1.35 (t, J=7.13 Hz, 3 H) 1.67 - 1.90 (m, 4 H) 2.03 - 2.18 (m, 1 H) 2.47 - 2.61 (m, 1 H) 2.72 (s, 3 H) 3.34 (br, s., 2 H) 3.56 - 3.87 (m, 4 H) 4.17 (s, 3 H) 4.35 (dd, J=7.13, 2.05 Hz, 2 H) 4.64 (s, 1 H) 5.89 - 6.04 (m, 1 H) 6.59 - 6.75 (m, 1 H) 7.45 (d, J=0.98 Hz, 1 H) 7.70 (d, J=8.20 Hz, 2 H) 7.77 (s, 1 H) 7.79 - 7.92 (m, 3 H)
bx 'H MR (400 MHz, MeOH-d4): δ ppm 1.35 (t, J=7.13 Hz, 3 H) 1.77 (br. s„ 4 H) 2.04 - 2.15 (m, 1 H) 2,47 - 2.58 (m, 1 H) 3.09 (s, 2 H) 3.57 (t, J=6.74 Hz, 6 H) 4.28 - 4.43 (m, 2 H) 4.57 - 4.69 (m, 1H) 5.80 - 5.92 (m, 1 H) 6.60 - 6.75 (m, 1 H) 7.62 (s, 1 H) 7.69 (d, J=8.40 Hz, 3 H) 7.74 - 7.85 (m, 2 H) 8.03 (d, J=8.00 Hz, 1 H)
by 'H NMR (400 MHz, MeOH-d4): 5 ppm 1.35 (t, J=7.13 Hz, 3 H) 1.61 - 1.81 (m, 4 H) 2.00 - 2.16 (m, 1 H) 2.44 - 2.59 (m, 1 H) 3.47 - 3.80 (m, 4 H) 4.35 (dd, J=7.03, 2.54 Hz, 2 H) 4.63 (s, 1 H) 5.73 (s,l H) 6.64 - 6.83 (m, 1 H) 7.76 (d, J=8.20 Hz, 2 H) 7.95 (d, J=8.20 Hz, 2 H) 8.12 - 8.33 (m, 2 H) 8.36 - 8.47 (m, 2 H) 8.48 - 8.68 (m, 1 H) 9.39 - 9.76 (m, 1 H)
bz lH NMR (400 MHz, MeOH-d4): δ ppm 1.10 - 1.20 (m, 3 H) 1.26 (t, J=7.13 Hz, 3 H) 1.42 - 1.64 (m, 4 H) 1.79 (dd, J=13.15, 7.44 Hz, 1 H) 1.94 (s, 2 H) 2.15 (dd, J=12,98, 8.69 Hz, 1 H) 2.35 (s, 3 H) 2.62 - 2.71 (m, 2 H) 2.81 - 2.87 (m, 1 H) 2.93 - 3.02 (m, 3 H) 3.40 - 3.66 (m, 4 H) 3.96 (t, J=8.18 Hz, 1 H) 4.06 (q, J=7.18 Hz, 2 H) 4.16 - 4.25 (m, 2 H) 5.69 (s, 1 H) 6.36 (d, J=2.25 Hz, 1 H) 6.71 (q, J=6.67 Hz, 1 H) 7.27 (d, J=1.56 Hz, 1 H) 7.35 (dd, J=8.13, 1.83 Hz, 1 H) 7.62 (d, J=8.20 Hz, 1 H) 7.83 (d, J=2.29 Hz, 3 H)
ca ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.35 (t, J=7.13 Hz, 3 H) 1.63 - 1.82 (m, 4 H) 2.03 - 2.17 (m, 1 H) 2.47 - 2.60 (m, 1 H) 3.51 - 3.83 (m, 4 H) 4.27 - 4.42 (m, 2 H) 4.57 - 4,69 (m, 1 H) 5.69 - 5,88 (m, 1 H) 6,65 - 6.85 (m, 1 H) 7.71 - 7.85 (m, 2 H) 7.89 - 8.01 (m, 2 H) 8.22 - 8.35 (m, 2 H) 8.36 - 8.49 (m, 1 H) 8.52 - 8.60 (m, 1 H) 8,62 - 8.72 (m, 1 H) 9.56 - 9.75 (m, 1 H)
cb !H NMR (400 MHz, DMSO-d6): δ ppm 1.18 (t, J=7.10 Hz, 3 H) 1.24 (t, J-7.13 Hz, 3 H) 1.37 - 1.63 (m, 4 H) 1.82 (quin, J-7.52 Hz, 2 H) 1.90 (dd, J=13,28, 9.42 Hz, 1 H) 2.19 - 2.41 (m, 6 H) 2.67 (t, J=7.69 Hz, 2 H) 3.12 (br. s., 2 H) 3.18 - 3.74 (m, 4 H) 4,05 (q, J=7.13 Hz, 2 H) 4.15 - 4.30 (m, 2 H) 4.52 (t, J=8.49 Hz, 1 H) 5.72 (br. s„ 1 H) 6.01 (br. s., 2 H) 6.37 (d, J=2.15 Hz, 1 H) 6.99 (q, J=6.87Hz, 1 H) 7.33 - 7.44 (m, 2 H) 7.47 (s, 1 H) 8.01 (d, J=2.25 Hz, 1 H) 9.20 (br. s., 1 H) 10.39 (br. s„ 1 H)
cc Ή NMR (400 MHz, DMSO-d6): δ ppm 1.10 - 1.20 (m, 3 H) 1.25 (t, J=7.10 Hz, 3 H) 1.44 - 1.63 (m, 4 H) 1.82 (quin, J=7.53 Hz, 2 H) 1.91 (dd, J=13.28, 9.37 Hz, 1 H) 2.19 - 2.40 (m, 3 H) 2.60 (t, J=7.71 Hz, 2 H) 3.13 (br. s., 2 H) 3.40 - 3.68 (m, 4 H) 4.02 (q, J=7.09 Hz, 2 H) 4.13 - 4.33 (m, 2 H) 4.53 (br. s., 1 H) 5.70 (br. s., 1 H) 6.29 (br. s, 2 H) 6.62 - 6.76 (m, 1 H) 7.28 (d, J=8.20 Hz, 2 H) 7.43 (d, J=8.10 Hz, 2 H) 9,21 (br. s., 1 H) 10.43 (br. s., 1 H)
cd H NMR (400 MHz, DMSO~d6): δ ppm 1.15 (t, J=7.13 Hz, 3 H) 1.24 (t, J=7.10 Hz, 3 H) 1.39 - 1.64 (m, 4 H) 1.78 - 1 ,97 (m, 3 H) 2,22 - 2.39 (m, 6 H) 2.66 (t, J=7,71 Hz, 2 H) 3.11 (br. s., 2 H) 3.38 - 3.64 (m, 4 H) 3.93 - 4,07 (m, 2 H) 4, 15 - 4.31 (m, 2 H) 4.52 (br. s., 1 H) 5.73 (br. s., 1 H) 6.05 (br. s., 2 H) 6.38 (d, J=2.10 Hz, 1 H) 7.00 (q, J=6.72 Hz, 1 H) 7.30 (d, J=1.51 Hz, 1 H) 7.33 - 7.41 (m,l H) 7.59 (d, J=8.05 Hz, 1 H) 8.04 (d, J=2.29 Hz, 1 H) 9.20 (br. s., 1 H) 10.38 (br. s., 1 H)
ce 'H NMR (400 MHz, MeOH-d4): δ ppm 1.22 - 1.30 (m, 3 H) 1.48 - 1.61 (m, 4 H) 1.82 (dd, J=13.30, 7.74 Hz, 1 H) 1.94 (s, 3 H) 2.15 - 2.23 (m, 1 H) 2,38 (s, 3 H) 2.87 - 2.92 (m, 1 H) 2.96 - 3.02 (m, 1 H) 3.42 - 3.64 (m, 4 H) 4.01 - 4.08 (m, 1 H) 4.16 - 4.25 (m, 2 H) 5.72 (s, 1 H) 6.41 (d, J=2.39 Hz, 1 H) 6.81 - 6.88 (m, 1 H) 7.61 - 7.66 (m, 1 H) 7.71 (d, J=1.76 Hz, 1 H) 7.73 - 7.86 (m, 3 H) 7.97 - 8.02 (m, 2 H) 8,08 (s, 1 H)cf lH NMR (400 MHz, DMSO-d6): δ ppm 1.25 (t, J=7.13 Hz, 3 H) 1.45 - 1.66 (m, 4 H) 1.92 (dd, J=13.18, 9.42 Hz, 1 H) 2.35 (dd, J=13.28, 8.54 Hz, 1 H) 3,14 (br. s., 2 H) 3.60 (br. s., 4 H) 4.14 - 4.31 (m, 2H) 4.54 (br. s„ 1 H) 5.75 (br. s„ 1 H) 6.56 (q, J=6.72 Hz, 1 H) 7.47 (t, J=1.27 Hz, 1 H) 7.65 (s, 2 H) 7.75 - 7,84 (m, 1 H) 7.89 (d, J=7.81 Hz, 1 H) 7.93 - 8.01 (m, 2 H) 9.21 (br. s„ 1 H) 10.36 (br. s., 1 H)
eg ¾ NMR (400 MHz, DMSO-d6): δ ppm 1.25 (t, J=7.10 Hz, 3 H) 1.57 (d, J=5.37 Hz, 4 H) 1.83 - 1.99 (m, 1 H) 2.28 - 2.40 (m, 1 H) 3.14 (br. s., 2 H) 3,58 (br. s., 4 H) 3.81 (s, 3 H) 4.24 (dd, J=7.13, 2.25 Hz, 2 H) 4.43 - 4.63 (m, 1 H) 5.62 - 5.85 (m, 1 H) 6.73 (d, J=6.78 Hz, 1 H) 6.96 - 7.16 (m, 3 H) 7.39 (d, J=2.15 Hz, 1 H) 7.50 (dd, J=8.74, 7.61 Hz, 1 H) 7.55 - 7.69 (m, 2 H) 9.09 - 9.32 (m, 1 H) 10.26 - 10.47 (m, 1 H)
ch 'H NMR (400 MHz, MeOH-d4): δ ppm 1.32 (t, J=7.15 Hz, 3 H) 1.52 - 1.70 (m, 4 H) 1.93 - 2.02 (m, 1 H) 2.40 (dd, J=13.45, 8.71 Hz, 1 H) 3.09 - 3.24 (m, 2 H) 3.43 - 3.74 (m, 4 H) 4.25 - 4.35 (m, 2 H) 4.40 (t, J=8.57 Hz, 1 H) 5.59 (s, 1 H) 6.61 (q, J=6.56 Hz, 1 H) 7.32 (d, J-2.15 Hz, 1 H) 7.49 (dd, J=8.49, 2.25 Hz, 1 H) 7.61 (d, J=8.00 Hz, 1 H) 7.65 - 7.77 (m, 2 H) 7.97 - 8.10 (m, 1 H) 8.32 (br. s., 1 H)
ci 'H NMR (400 MHz, MeOH-d4): δ ppm 1.32 (t, J=7.13 Hz, 3 H) 1.50 - 1.70 (m, 4 H) 1.91 - 2.02 (m, 1 H) 2.39 (dd, J= 13.50, 8.76 Hz, 1 H) 3.08 - 3.23 (m, 2 H) 3.41 - 3.69 (m, 4 H) 4.24 - 4.34 (m, 2 H) 4.38 (t, J=8.54 Hz, 1 H) 5.50 (s, 1 H) 6.75 (q, J=6.96 Hz, 1 H) 6.87 (d, J=7.66 Hz, 1 H) 6.91 (ddd, J=8.21, 2.50, 0.90 Hz, 1 H) 7.06 (br. s., 1 H) 7.28 (d, J=2.20 Hz, 1 H) 7.32 (t, J=7.88 Hz, 1 H) 7.43 (dd, J=8.47, 2.27 Hz, 1 H) 7.66 (d, J=8.44 Hz, 1 H)
cj Ή NMR (400 MHz, MeOH-d4): δ ppm 1.32 (t, J=7.13 Hz, 3 H) 1.52 - 1.70 (m, 4 H) 1.93 - 2.06 (m, 1 H) 2.41 (dd, J=13,42, 8.74 Hz, 1 H) 3.10 - 3.25 (m, 5 H) 3.44 - 3.74 (m, 4 H) 4.21 - 4.37 (m, 2 H) 4.42 (t, J=8.59 Hz, 1 H) 5.61 (s, 1 H) 6.57 (q, J=6.57 Hz, 1 H) 7.36 (d, J=2.20 Hz, 1 H) 7.51 (dd, J=8.54, 2.20 Hz, 1 H) 7.70 (d, J=8.44 Hz, 1 H) 7.72 - 7.78 (m, 1 H) 7.78 - 7.89 (m, 1 H) 8.09 (dt, J=7.85, 1.49 Hz, 1 H) 8.41 (d, J=0.73 Hz, 1 H)
ck 'H NMR (400 MHz, DMSO-d6): δ ppm 1.21 (t, J=7.10 Hz, 3 H) 1.38 - 1.64 (m, 4 H) 1.88 (dd, 1=13.20, 9.35 Hz, 1 H) 2.30 (dd, J=13.20, 8.47 Hz, 1 H) 3.09 (br. s„ 2 H) 3.42 - 3.61 (m, 4 H) 3.95 - 4.11 (m,2 H) 4.12 - 4.28 (m, 2 H) 4.48 (br. s., 1 H) 5.71 (br. s., 1 H) 6.32 (br. s., 1 H) 6.71 (q, J-6.74 Hz, 1 H) 7.33 (d, J=2.05 Hz, 1 H) 7.44 - 7.69 (m, 6 H) 8.52 (br. s„ 3 H) 9.27 (br. s., 1 H) 10.62 (br. s., 1 H)
cl 'H NMR (400 MHz, MeOH-d4): δ ppm 1.35 (t, J=7.13 Hz, 4 H) 1 ,82 (br. s., 4 H) 2.03 - 2.21 (m, 1 H) 2.47 - 2.64 (m, 1 H) 3.35 (s, 2 H) 3.56 - 3.92 (m, 4 H) 4.27 - 4.43 (m, 2 H) 4.59 - 4.70 (m, 1 H) 6.65 - 6.82 (m, 1 H) 7.81 (d, J=8.00 Hz, 2 H) 8.00 (d, J=8,20 Hz, 2 H) 8.05 - 8.14 (m, 1 H) 8.29 - 8.40 (m, 1 H) 8.46 - 8.55 (m, 1 H) 8.63 (d, J=1.56 Hz, 1 H) 9.21 (s, 2 H)
cm Ή NMR (400 MHz, MeOH-d4): δ ppm 1.35 (t, J=6.93 Hz, 5 H) 1.83 (br. s., 4 H) 2.04 - 2.22 (m} 1 H) 2.47 - 2,65 (m, 1 H) 3.36 (br. s., 2 H) 4.35 (d, J=6.64 Hz, 2 H) 4.57 - 4.71 (m, 1 H) 6.64 - 6.85 (m, 1 H) 7.84 (d, J=6.64 Hz, 2 H) 8.03 (d, J=6.83 Hz, 2 H) 8,08 - 8.18 (m, 1 H) 8.27 - 8.41 (m, 1 H) 8.50 (br. s., 2 H) 9.26 (br. s., 2 H) cn Ή NMR (400 MHz, MeOH-d4): δ ppm 1.24 - 1.45 (m, 10 H) 1.75 (d, J=18.55 Hz, 4 H) 2.01 - 2.18 (m, 1 H) 2.43 (s, 3 H) 2.47 - 2.62 (m, 1 H) 3.86 (br. s., 3 H) 4.34 (d, J=5.86 Hz, 2 H) 4.54 - 4.75 (m, 2 H) 6.44 (d, J=l ,95 Hz, 1 H) 6.89 (d, J=5.66 Hz, 1 H) 7.03 (d, J=8.59 Hz, 2 H) 7.57 - 7.71 (m, 3 H) 7.72 - 7.87 (m, 2 H) 7.98 (d, J=1.76 Hz, 1 H)
co 'H MR (400 MHz, MeOH-d4): δ ppm 1.35 (s, 3 H) 1.64 - 1.91 (m, 4 H) 2.03 - 2.20 (m, 1 H) 2.47 - 2.64 (m, 1 H) 3.35 (br. s., 2 H) 3.56 - 3.95 (m, 4 H) 4.25 - 4.44 (m, 2 H) 4.57 - 4.71 (m, 1 H) 6.57- 6,84 (m, 1 H) 7.70 - 7.85 (m, 2 H) 7.90 - 8,07 (m, 2 H) 8,23 (s, 2 H) 8.33 - 8.47 (m, 1 H) 8.86 - 9.05 (m, 2 H)
cp 'H NMR (400 MHz, MeOH-d4): δ ppm 1.18 - 1.31 (m, 3 H) 1.44 - 1 ,60 (m, 4 H) 1 ,79 (dd, J=13.28, 7.61 Hz, 1 H) 1.93 (s, 2 H) 1.98 (s, 3 H)2.14 (dd, J=13.1 , 8.79 Hz, 1 H) 2.37 (s, 3 H) 2.80 - 2.89 (m, 1 H) 2.91 - 3,00 (m, 1 H) 3.40 - 3.64 (m, 4 H) 3.97 (t, 14054202
Figure imgf000332_0001
J=6.80 Hz, 1 H) 7.30 (d, J-2.20 Hz, 1 H) 7.47 (dd, J=8.52, 2.22 Hz, 1 H) 7.52 - 7.59 (m, 1 H) 7.59 - 7.65 (m, 1 H) 7.67 (d, J=8.54 Hz, 1 H) 7.90 - 8.04 (m, 1 H) 8.41 (br. s„ 1 H)
cy ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.33 (t, J=7.15 Hz, 3 H) 1.53 - 1.74 (m, 4 H) 2.05 (dd, J=13.57, 8.79 Hz, 1 H) 2.48 (dd, J=13.54, 8.76 Hz, 1 H) 3.23 (s, 3 H) 3.27 (d, J=l .22 Hz, 2 H) 3.42 - 3.79 (m, 4 H) 4.22 - 4.42 (m, 2 H) 4.57 (t, J=8.79 Hz, 1 H) 5.54 (s, 1 H) 6.61 (q, J=6.72 Hz, 1 H) 7.35 (d, J=2.20 Hz, 1 H) 7.52 (dd, J=8.54, 2.25 Hz, 1 H) 7.72 (d, J=8.54 Hz, 1 H) 7.77 (d, J=7.86 Hz, 2 H) 8.08 - 8.20 (m, 2 H)cz 'H NMR (400 MHz, MeOH-d4): δ ppm 1.33 (t, J=7.13 Hz, 3 H) 1.54 - 1.72 (m, 4 H) 1.99 - 2.07 (m, 1 H) 2.46 (dd, J=13.57, 8.74 Hz, 1 H) 3.17 - 3.28 (m, 2 H) 3.42 - 3.72 (m, 4 H) 4.26 - 4.39 (m, 2 H) 4.51 (t, J=8,69 Hz, 1 H) 5.53 (s, 1 H) 6.56 - 6.66 (m, 1 H) 7.34 (d, J=2.20 Hz, 1 H) 7.51 (dd, J=8,52, 2.22 Hz, 1 H) 7.67 (d, J=8.00 Hz, 2 H) 7.71 (d, J=8.49 Hz, 1 H) 8.02 - 8.14 (m, 2 H)
da !H NMR (400 MHz, MeOH-d4): δ ppm 0.99 (t, J=7.15 Hz, 3 H) 1.33 (t, J=7.13 Hz, 3 H) 1.62 - 1.78 (m, 4 H) 2.07 (dd, J=13.64, 8.86 Hz, 1 H) 2.41 (s, 3 H) 2.50 (dd, J=13.67, 8.79 Hz, 1 H) 3.29 - 3.31 (m, 2 H) 3.55 - 3.84 (m, 4 H) 3.84 - 4.06 (m, 2 H) 4.23 - 4.42 (m, 2 H) 4.60 (t, J=8.81 Hz, 1 H) 6.23 - 6.36 (m, 1 H) 6.43 (d, J=2.34 Hz, 1 H) 6.89 - 7.01 (m, 1 H) 7.40 (dd, J=7.66, 0.93 Hz, 1 H) 7.48- 7.59 (m, 4 H) 7.60 - 7.69 (m, 1 H) 7.86 (dd, J=7.79, 1.24 Hz, 1 H) 7.93 (d, J=2.34 Hz, 1 H)
db Ή NMR (400 MHz, MeOH-d4): 5 ppm 1.30 (t, J=7.15 Hz, 3 H) 1.40 (t, J=7.13 Hz, 3 H) 1.52 - 1.67 (m, 4 H) 2.00 (dd, J=13.59, 8.81 Hz, 1 H) 2.39 (s, 3 H) 2.44 (dd, J=13.64, 8.76 Hz, 1 H) 3.17 - 3.27 (m, 2 H) 3.41 - 3.73 (m, 4 H) 4.23 - 4.36 (m, 2 H) 4.40 (q, J=7.13 Hz, 2 H) 4.54 (t, J=8.79 Hz, 1 H) 5.78 (s, 1 H) 6.41 (d, J=2.15 Hz, 1 H) 6.92 (q, J=6.62 Hz, 1 H) 7.52 (d, J=8.25 Hz, 1 H) 7.58 (t, J=7.74 Hz, 1 H) 7.77 - 7.87 (m, 2 H) 7.88 - 7.97 (m, 2 H) 8.03 (dt, J=7.79, 1.33 Hz, 1 H) 8.21 (t, J=1.61 Hz, 1 H)
dc 'H MR (400 MHz, MeOH-d4): δ ppm 1.32 (t, J=7.13 Hz, 3 H) 1.41 (t, J=7.13 Hz, 3 H) 1.56 - 1.69 (m, 4 H) 2.03 (dd, J=13.62, 8.83 Hz, 1 H) 2.41 (s, 3 H) 2.47 (dd, J=13.57, 8.79 Hz, 1 H) 3.26 (s, 2 H) 3.46 - 3.75 (m, 4 H) 4.32 (qd, J=7.15, 2.37 Hz, 2 H) 4.40 (q, J=7.14 Hz, 2 H) 4.57 (t, J-8.79 Hz, 1 H) 5.87 (s, 1 H) 6.43 (d, J=2.34 Hz, 1 H) 6.89 - 7.03 (m, 1 H) 7.55 (d, J=8.30 Hz, 1 H) 7.68 - 7.79 (m, 2 H) 7.87 (dd, J=8.30, 2.15 Hz, 1 H) 7.94 (d, J=2.34 Hz, 1 H) 7.98 (d, J=1.51 Hz, 1 H) 8.08 - 8.18 (m, 2 H)
dd Ή NMR (400 MHz, MeOH-d4): δ ppm 1.32 (t, J=7.15 Hz, 3 H) 1.50 - 1.71 (m, 4 H) 2.00 (dd, J=13.54, 8.61 Hz, 1 H) 2.38 (s, 3 H) 2.42 (dd, J=13.59, 8.81 Hz, 1 H) 3.12 - 3.28 (m, 2 H) 3.42 - 3.77 (m, 6 H) 4.21 - 4.39 (m, 2 H) 4.48 (t, J=8.69 Hz, 1 H) 4.69 - 4.79 (m, 1 H) 5.72 (d, J=2.05 Hz, 1 H) 6.39 (d, J=2.29 Hz, 1 H) 6.77 (q, J=6.54 Hz, 1 H) 7.45 (d, J=1.56 Hz, 1 H) 7.52 (dd, J=8.20, 1.56 Hz, 1H) 7.70 (d, J=8.15 Hz, 1 H) 7.88 (dd, J=4.37, 2.37 Hz, 1 H)
de !H NMR (400 MHz, MeOH-d4): δ ppm 1.22 - 1.29 (m, 3 H) 1.51 (dt, J=l 1.74, 5.65 Hz, 4 H) 1.75 (dd, J=12.98, 7.32 Hz, 1 H) 1.90 (s, 4 H) 2.09 (dd, J=13.13, 8.74 Hz, 1 H) 2.38 (s, 3 H) 2.73 - 2.93 (m,2 H) 3.43 - 3.63 (m, 4 H) 3,85 (dd, J 8.71, 7.39 Hz, 1 H) 4.10 (s, 2 H) 4.13 - 4.23 (m, 2 H) 5.70 (s, 1 H) 6.41 (d, J=2.25 Hz, 1 H) 6.78 (q, J=6.88 Hz, 1 H) 7.52 (d, J=8.35 Hz, 2 H) 7.66 (d, J=1.71 Hz, 1 H) 7.72 - 7.84 (m, 4 H) 7.97 (d, J=2.34 Hz, 1 H)
df ¾ NMR (400 MHz, MeOH-d4): δ ppm 1 .33 (dt, J=10.30, 7,13 Hz, 6 H) 1.50 - .69 2
Figure imgf000334_0001
14054202
Figure imgf000335_0001
1.90 (dd, J=13.35, 8.22 Hz, 1 H) 2.30 (dd, J=13.35, 8.71 Hz, 1 H) 2.40 (s, 3 H) 2.93 - 3.16 (m, 2 H) 3.38 - 3.74 (m, 4 H) 4.16 - 4.36 (m, 3 H) 5.77 (s, 1 H) 6.41 (d, J=2.29 Hz, 1 H) 6.91 (q, J=6.62 Hz, 1 H) 7.51 (d, J=8.25 Hz, 1 H) 7.64 (d, J=8.40 Hz, 2 H) 7.82 (dd, J=8.30, 2.15 Hz, 1 H) 7.93 (d, J=2.29 Hz, 1 H) 7.96 (s, 1 H) 8.07 (d, J=8.30 Hz, 2 H)
dv Ή NMR (400 MHz, MeOH-d4): δ ppm 1.35 (s, 4 H) 1,60 - 1.76 (m, 3 H) 2.02 - 2.13 (m, 1 H) 2.43 (s, 3 H) 2,46 - 2.56 (m, 1 H) 3.30 (s, 2 H) 3.53 - 3.83 (m, 4 H) 4.30 - 4.40 (m, 2 H) 4.56 - 4.66 (m, 1 H) 5.48 (s, 2 H) 6.01 - 6.1 1 (m, 1 H) 6.44 - 6.50 (m, 1 H) 6.89 - 6.98 (m, 1 H) 7.80 - 7,84 (m, 1 H) 7.86 - 8.02 (m, 5 H) 8.03 - 8.08 (m, I H)dw 'H MR (400 MHz, MeOH -d4): δ ppm 1.28 (t, J=7.13 Hz, 3 H) 1.55 (br. s., 4 H) 1.70 - 1.83 (m, 1 H) 2.03 - 2.18 (m, 1 H) 2.70 - 2.82 (m, 1 H) 2.86 - 2.97 (m, 1 H) 3.41 - 3.59 (tn, 4 H) 3.79 - 3.94 (m, 1 H) 4.09 - 4.30 (m, 2 H) 5.59 (s, 1 H) 6.60 - 6.77 (m, 1 H) 7.71 (d, J=8.20 Hz, 2 H) 7.84 (d, J=8.20 Hz, 2 H) 8.03 - 8.15 (m, 1 H) 8.34 (s, 2 H) 9.26 (s, 1 H) 9.59 (s, 1 H)
dx 'H NMR (400 MHz, Chloroform-*/): δ ppm 1.27 (m, 7H), 1.55 (m, 3H), 1 ,77 (dd, J = 13.1, 7.0 Hz, 1H), 2.1 1 (dd, J = 13.1, 8.9 Hz, 1H), 2.42 (s, 3H), 2.96 (m, 2H), 3.47 (dt, J = 1 1.6, 5.7 Hz, 4H), 3.98 (dd, J = 8.8, 6.9 Hz, 1H), 4.21 (q, J = 7, 1 Hz, 2H), 4.73 (s, 2H), 5.49 (s, 1H), 5.99 (m, 1H), 6.35 (d, J = 2.3 Hz, 1H), 6.63 (q, J = 6.7 Hz, 1H), 7.61 (m, 2H), 7.73 (d, J = 2.3 Hz, 1H), 7.88 (d, J = 8.3 Hz, 1H), 8.96 (s, 2H), 9.24 (s, 1H)
dy Ή NMR (400 MHz, MeOH-d4): 5 ppm 1.27 (m, 8H), 1.51 (dt, J - 10.8, 5.6 Hz, 8H), 1.74 (dd, J = 13,1 , 7.3 Hz, 2H), 2.06 (m, 2H), 2.39 (s, 6H), 2.75 (d, J = 11.0 Hz, 2H), 2.89 (d, J = 11.0 Hz, 2H), 3.53 (dt, J = 22.5, 6.4 Hz, 8H), 3.82 (dd, J = 8.8, 7.2 Hz, 2H), 4.18 (qd, J = 7.1, 1.6 Hz, 3H), 5.73 (s, 2H), 6.00 (m, 1H), 6.42 (d, J = 2.4 Hz, 2H), 6.82 (q, J = 6.6 Hz, 2H), 7.35 (dt, J = 10.4, 8.4 Hz, 2H), 7.50 (m, 2H), 7.73 (m, 8H), 8.00 (d, J = 2.4 Hz, 2H)
dz Ή NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.50 (dt, J = 10.6, 5.6 Hz, 4H), 1.73 (dd, J = 13,1 , 7.2 Hz, 1H), 2.07 (dd, J = 13.1, 8.8 Hz, 1H), 2.39 (s, 3H), 2.74 (d, J = 1 1.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.52 (dq, J - 23.8, 7.6, 6.5 Hz, 4H), 3.81 (dd, J = 8.8, 7.1 Hz, 1H), 4.17 (qd, J = 7.1, 1.6 Hz, 2H), 5.73 (s, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.80 (q, J = 6.5 Hz, 1H), 7.46 (m, 2H), 7.71 (m, 5H), 7.98 (d, J = 2.3 Hz, 1H)
ea ¾ NMR (400 MHz, DMSO-d6): δ ppm 1.25 (t, J=7.10 Hz, 3 H) 1.42 - 1 ,69 (m, 4 H) 1 ,92 (dd, J=13,25, 9.35 Hz, 1 H) 2.35 (dd, J=13.25, 8.47 Hz, 1 H) 3.14 (br. s., 2 H) 3.60 (br. s., 4 H) 4.24 (qd, J=7.09, 2.10 Hz, 2 H) 4.54 (br. s., 1 H) 5.77 (br. s., 1 H) 6.70 (q, J=6.65 Hz, 1 H) 7.37 (d, J=2.10 Hz, 1 H) 7.43 - 7.52 (m, 3 H) 7.53 - 7.69 (m, 4 H) 9.23 (br. s., 1 H) 10.44 (br. s., 1 H)
eb Ή NMR (400 MHz, MeOH-d4): δ ppm 1.25 (t, J = 7.1 Hz, 4H), 1.49 (dt, J = 10.6, 5,6 Hz, 4H), 1,73 (dd, J = 13, 1, 7.2 Hz, 1H), 2.06 (dd, J = 13.1, 8.8 Hz, 1H), 2.39 (s, 3H), 2.74 (d, J = 11.0 Hz, 1 H), 2.88 (d, J = 1 1.0 Hz, 1H), 3.50 (m, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, 1H), 4.17 (qd, J = 7.1, 1.5 Hz, 2H), 5.76 (s, 1H), 6.41 (d, J = 2,4 Hz, 1H), 6.89 (q, J = 6.6 Hz, 1H), 7.51 (m, 6H), 7.76 (dd, J = 8.3, 2.2 Hz, 1H), 7.92 (t, J = 2.2 Hz, 2H) ec JH NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 5H), 1.51 (dt, J = 10.1, 5.3 Hz, 4H), 1.77 (dd, J = 13.1, 7.4 Hz, IH), 2.12 (dd, J = 13.2, 8.8 Hz, IH), 2.39 (s, 3H), 2.80 (d, J = 1 1.1 Hz, IH), 2.93 (d, J = 11.1 Hz, IH), 3.53 (m, 4H), 3.91 (t, J = 8.0 Hz, IH), 4.19 (qd, J = 7.2, 1.7 Hz, 2H)} 5.77 (s, IH), 6.41 (d, J = 2.3 Hz, IH), 6.91 (q, J = 6.6 Hz, IH), 7.37 (ddt, J = 16.6, 10.3, 8.6 Hz, 2H), 7.51 (m, 2H), 7.76 (dd, J = 8.3, 2.2 Hz, IH), 7.91 (dd, J = 9.9, 2.4 Hz, 2H)
ed Ή NMR (400 MHz, MeOH-d4): δ ppm 1.26 (m, 6H), 1.50 (dt, J =* 10.4, 5.4 Hz, 5H), 1.73 (dd, J = 13.1 , 7.2 Hz, IH), 2,06 (m, IH), 2.39 (s, 3H), 2.74 (d, J = 1 1.0 Hz, IH), 2.88 (d, J = 1 1.0 Hz, IH), 3.53 (m, 5H), 3.81 (dd, J - 8.7, 7.1 Hz, IH), 4.17 (qd, J = 7.1, 1.5 Hz, 2H), 5.77 (s, IH), 6.41 (d, J = 2.4 Hz, IH), 6.87 (q, J = 6.7 Hz, IH), 7.44 (m, 4H), 7.60 (m, 3H), 7.78 (dd, J = 8.3, 2.1 Hz, IH), 7.92 (t, J = 2.6 Hz, 2H) ee Ή NMR (400 MHz, MeOH-d4): δ ppm 1.27 (q, J = 8.3, 7.1 Hz, 6H)5 1.49 (m, 4H), 1.72 (dd, J = 13.1, 7.2 Hz, IH), 2.06 (dd, J = 13.1, 8.8 Hz, IH), 2.39 (s, 3H), 2.74 (d, J = 1 1.0 Hz, IH), 2.88 (d, J = 1 1.0 Hz, IH), 3.50 (m, 4H), 3.83 (dd, J = 8,8, 7.2 Hz, IH), 4.18 (qd, J = 7.1, 1.5 Hz, 2H), 5.77 (s, IH), 6,41 (d, J = 2.5 Hz, IH), 6.93 (q, J = 6.6 Hz, IH), 7.50 (m, 2H), 7.59 (d, J = 8.3 Hz, IH), 7.73 (m, 2H), 7.92 (dd, J = 7.7, 2.3 Hz, 2H)
ef >H NMR (400 MHz, MeOH-d4): δ ppm 1.28 (t, J = 7.1 Hz, 5H), 1.54 (tt, J = 7.3, 4.4 Hz, 4H), 1.80 (dd, J = 13.2, 7.6 Hz, IH), 2.17 (dd, J = 13.2, 8.8 Hz, IH), 2.85 (d, J = 1 1.2 Hz, lH)s 2.97 (d, J = 1 1.2 Hz, 1H), 3.52 (ddt, J = 28.3, 12.4, 8,0 Hz, 4H), 3.97 (dd, J = 8.8, 7.5 Hz, IH), 4.21 (qd, J = 7.1, 1.7 Hz, 2H), 5.50 (s, IH), 6.68 (q, J = 6.9 Hz, IH), 7.25 (m, 4H), 7.48 (m, 3H), 7.71 (m, IH)
eg [H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.3 Hz, 4H), 1.51 (dt, J = 1 1.2, 5.5 Hz, 4H), 1.75 (dd, J = 13.1, 7.3 Hz, IH), 2.10 (dd, J = 13.1 , 8.8 Hz, IH), 2.40 (s, 3H), 2.78 (d, J = 11.1 Hz, IH), 2.91 (d, J = 11.0 Hz, IH), 3.53 (m, 5H), 3.86 (dd, J = 8.6, 7.4 Hz, IH), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.77 (s, IH), 6.44 (d, J = 2.4 Hz, IH), 7.00 (q, J - 6.7 Hz, IH), 7.62 (d, J = 8.3 Hz, IH), 7.97 (m, 3H), 9.06 (s, 2H), 9.17 (s, IH)eh lH NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 4H), 1.52 (dq, J = 12.0, 8.6, 7.2 Hz, 4H), 1,74 (dd, J = 13.1, 7.2 Hz, IH), 2.09 (dd, J = 13.1, 8.8 Hz, IH), 2.75 (d, J = 11.0 Hz, IH), 2.90 (d, J = 1 1.0 Hz, IH), 3.51 (m, 4H), 3.82 (dd, J = 8.7, 7.1 Hz, IH), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.52 (s, IH), 6.61 (q, J = 6.7 Hz, IH), 7.33 (m, 2H), 7.47 (m, 2H), 7.66 (m, 2H)
ei Ή NMR (400 MHz, MeOH-d4): δ ppm 1.26 (td, J = 7.1 , 1.7 Hz, 6H), 1.41 (td, J = 7.0, 1.8 Hz, 3H), 1.52 (qd, J = 7.2, 4.7, 3.6 Hz, 4H), 1.75 (dd, J = 13,1, 7.3 Hz, IH), 2,10 (dd, J = 13.1, 8.8 Hz, IH), 2.77 (d, J = 10.9 Hz, IH), 2.91 (d, J = 11.0 Hz, IH), 3.29 (s, IH), 3.51 (dq, J = 18.9, 6.1 Hz, 4H), 3.84 (m, IH), 4.16 (m, 3H), 5.48 (d, J = 2.0 Hz, IH), 6.73 (q, J = 6.8 Hz, IH), 7.02 (m, 2H), 7.20 (s, IH), 7.28 (d, J = 2.2 Hz, IH), 7.43 (m, 2H), 7.67 (d, J - 8.4 Hz, IH)
ej Ή NMR (400 MHz, MeOH-d4): δ ppm 1.26 (m, 4H), 1.50 (dt, J = 22.1, 6.5 Hz, 7H), 1.74 (dd, J = 13.1, 7.2 Hz, H), 2.08 (dd, J = 13.1 , 8.8 Hz, IH), 2.75 (d, J = 1 1.0 Hz, IH), 2.90 (d, J = 11.0 Hz, IH), 3.31 (d, J = 1.8 Hz, IH), 3.49 (dq, J = 25.8, 7.5, 6.6 Hz, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, IH), 4.18 (m, 4H), 5.49 (s, IH), 6.62 (q, J = 6.8 Hz, IH), 7.20 (d, J = 8.5 Hz, IH), 7.26 (d, J = 2.2 Hz, IH), 7.34 (m, IH), 7.42 (dd, J = 8.5, 2.2 Hz, IH), 7.58 (m, IH), 7.65 (d, J = 8.5 Hz, IH)
ek Ή NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.0 Hz, 4H), 1 ,53 (m, 4H), 1.75 (dd, J = 13.1 , 7.2 Hz, lH), 2.10 (dd, J = 13.1, 8.7 Hz, IH), 2.76 (d, J = 10.9 Hz, H), 2.90 (d, J = 1 1.0 Hz, IH), 3.51 (dq, J = 26.1, 7.5, 6.6 Hz, 4H), 3.83 (dd, J = 8.8, 7.2 Hz, IH), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.53 (s, IH), 6.59 (q, J = 6.7 Hz, IH), 7.27 (d, J = 8.8 Hz, IH), 7.34 (m, 2H), 7.49 (m, 2H), 7.69 (d, J = 8.5 Hz, IH)
el 'H NM (400 MHz, MeOH-d4): δ ppm 0.89 (m, 2H), 1.31 (ra, 15H), 1.52 (dt, J = 7.9, 4.5 Hz, 4H), 1.74 (dd, J = 13.1, 7.2 Hz, IH), 2.09 (dd, J = 13.1, 8,8 Hz, 1H), 2.75 (d, J = 11.0 Hz, IH), 2.89 (d, J = 1 1.0 Hz, IH), 3.49 (ddt, J - 17.6, 1 1.8, 6.7 Hz, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, IH), 4.18 (qd, J = 7.2, 1.5 Hz, 2H), 5.44 (s, IH), 6.60 (q, J = 6.8 Hz, IH), 7.28 (m, 2H), 7.47 (m, 4H), 7.67 (d, J = 8,5 Hz, IH)
eni 'H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (m, 6H), 1 ,53 (m, 4H), 1.75 (dd, J =
13.1, 7.2 Hz, IH), 2.10 (dd, J = 13.1, 8.7 Hz, IH), 2.76 (d, J = 10.9 Hz, IH), 2.91 (d, J = 11.0 Hz, IH), 3.52 (m, 4H), 3.83 (dd, J = 8.8, 7.2 Hz, IH), 4.18 (qd, J = 7.1, 1.7 Hz, 2H)5 5.53 (s, IH), 6.47 (q, J = 6.7 Hz, IH), 7.36 (d, J = 2.2 Hz, IH), 7.53 (dd, J = 8.6, 2.3 Hz, IH), 7.72 (m, 2H), 7.85 (m, 2H)
en 'H NMR (400 MHz, MeOH-d4): δ ppm 1.30 (t, J = 7.1 Hz, 7H), 1.59 (dt, J = 1 1.5, 5.7 Hz, 8H), 1.95 (m, 2H), 2.34 (dd, J = 13.3, 8.6 Hz, 2H), 3.10 (m, 4H), 3.56 (m, 8H), 3.75 (s, IH), 4.28 (m, 6H), 5.55 (s, IH), 6.52 (q, J - 6.7 Hz, 2H), 7.38 (d, J = 2.2 Hz, 2H), 7.53 (dd, J = 8.5, 2.2 Hz, 2H), 7.66 (m, 8H)
eo ¾ NMR (400 MHz, MeOH-d4): 5 ppm 1.26 (td, J = 7.0, 0.7 Hz, 4H), 1.53 (m, 4H), 1.75 (dd, J = 13.1, 7.3 Hz, IH), 2.09 (dd, J = 13.1, 8.7 Hz, IH), 2.76 (d, J = 1 1.0 Hz, IH), 2.90 (d, J = 11.0 Hz, IH), 3.30 (m, IH), 3.51 (dtd, J = 19.2, 13.4, 7.5 Hz, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, IH), 4.18 (m, 2H), 5.50 (s, IH), 6.63 (q, J = 6.9 Hz, IH), 7.25 (m, IH), 7.47 (m, 6H), 7.71 (m, IH)
ep ¾ NMR (400 MHz, MeOH-d4): 6 ppm 1.33 (t, J = 7, 1 Hz, 4H), 1.65 (m, 5H), 2.06 (dd, J = 13.6, 8.9 Hz, IH), 2.50 (dd, J = 13.6, 8.8 Hz, I H), 3.28 (s, 2H), 3.57 (m, 5H), 3.86 (s, 3H), 4.32 (qd, J = 7.2, 2.5 Hz, 2H), 4.59 (t, J = 8.8 Hz, IH), 6.68 (q, J = 6,7 Hz, IH), 6,98 (d, J = 7.5 Hz, IH), 7.07 (m, 2H), 7.32 (d, J = 2.2 Hz, IH), 7.46 (m, 2H), 7.68 (d, J = 8.5 Hz, IH)
eq Ή NMR (400 MHz, MeOH-d4): δ ppm 1.31 (m, 10H), 1.52 (m, 4H), 1.74 (dd, J = 13.1, 7.2 Hz, IH), 2.09 (dd, J = 13.1, 8.7 Hz, IH), 2.75 (d, J = 1 1.0 Hz, IH), 2.90 (d, J = 1 1.0 Hz, IH), 3.50 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, IH), 4.18 (qd, J = 7, 1, 1.5 Hz, 2H), 4.70 (h, 3 = 6.1 Hz, IH), 5.48 (s, IH), 6.73 (q, J = 6.9 Hz, IH), 6.95 (d, J = 7.6 Hz, IH), 7.04 (m, IH), 7.21 (s, IH), 7.27 (d, J = 2.3 Hz, IH), 7.42 (m, 2H), 7.66 (d, J = 8.5 Hz, IH)
er 'H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (td, J = 7.1 , 1.4 Hz, 3H), 1.54 (m, 4H), 1.75 (dd, J = 13.1 , 7.2 Hz, IH), 2.10 (dd, J = 13.1, 8.7 Hz, IH), 2.46 (s, 3H), 2.76 (d, J = 10.9 Hz, IH), 2.91 (d, J = 11.0 Hz, IH), 3.52 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, IH), 4, 18 (qd, J = 7.2, 1.6 Hz, 2H), 5.50 (d, J = 1.5 Hz, IH), 6.60 (q, J = 6.8 Hz, IH), 7.29 (m, 2H), 7.45 (m, 2H), 7.57 (s, IH), 7.67 (m, IH)
es Ή NMR (400 MHz, MeOH-d4): δ ppm: 1.19 (s, 2H), 1.34 (m, 1 IH), 1.53 (m, 4H), 1,75 (dd, J = 13.1, 7.2 Hz, IH), 2.10 (dd, J = 13.1, 8.8 Hz, IH), 2.76 (d, J = 1 1.0 Hz, IH), 2.91 (d, J = 1 1.0 Hz, I H), 3.52 (m, 4H), 3.83 (m, IH), 4.18 (m, 2H), 4.73 (h, J = 6.1 Hz, IH), 5.50 (s, IH), 6.62 (q, J = 6.6 Hz, IH), 7.28 (m, 3H), 7.43 (dd, J = 8.5, 2.3 Hz, IH), 7.59 (s, IH), 7.65 (d, J - 8.5 Hz, IH)
et ¾ NMR (400 MHz, MeOH-d4): δ ppm 0.88 (d, J = 8.3 Hz, IH), 1.30 (m, 1 IH), 1.53 (m, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.10 (dd, J = 13.1 , 8.8 Hz, IH), 2.76 (d, J = 11.0 Hz, IH), 2.91 (d, J = 1 1.0 Hz, IH), 3.52 (m, 5H), 3,83 (dd, J = 8.7, 7.2 Hz, IH), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 4.71 (h, J = 6.2 Hz, 1H), 5.49 (s, 1H), 6.66 (q, J = 6.8 Hz, 1H), 7.27 (m, 4H), 7.43 (dd, J = 8.5, 2.3 Hz, 1H), 7.65 (m, 1H)
eu Ή NMR (400 MHz, MeOH-d4): δ ppm 1.30 (m, 4H), 1.60 (tt, J = 9.2, 4.2 Hz, 4H), 1.97 (m, 1H), 2.37 (dd, J = 13.6, 8.8 Hz, IH), 3.14 (q, J = 1 1.6 Hz, 2H), 3.56 (m, 4H), 4.31 (m, 3H), 4.87 (d, J = 1.7 Hz, 18H), 5.54 (s, IH), 6.49 (q, J - 6.6 Hz, IH), 7.35 (d, J = 2.2 Hz, 1H), 7.51 (dd, J = 8.5, 2.2 Hz, 1H), 7.68 (d, J = 8.6 Hz, IH), 7.82 (m, 3H)ev !H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (m, 4H), 1.54 (m, 4H), 1.78 (dd, J =
13.1 , 7.4 Hz, IH), 2.13 (dd, J = 13.1, 8.8 Hz, IH), 2.81 (d, J = 11.1 Hz, IH), 2.93 (d, J = 1 1.0 Hz, IH), 3.53 (dq, J = 13.2, 6.0 Hz, 4H), 3.89 (dd, J = 8.8, 7.3 Hz, I H), 4.20 (qd, J = 7.1, 1.7 Hz, 2H), 5.51 (s, IH), 6.63 (q, J = 6.7 Hz, IH), 7.28 (m, 4H), 7.52 (m, 2H), 7.68 (d, J = 8.5 Hz, IH)
ew ¾ NMR (400 MHz, MeOH-d4): δ ppm 0.90 (d, J = 8.0 Hz, IH), 1.27 (m, 5H), 1.53 (dt, J = 7.7, 4.7 Hz, 4H), 1.76 (dd, J = 13.1 , 7.2 Hz, IH), 2.11 (dd, J = 13.1 , 8.8 Hz, 1H), 2.45 (s, 3H), 2.78 (d, J = 1 1.0 Hz, 1H), 2.91 (d, J = 1 1.0 Hz, 1H), 3.31 (s, 3H), 3.50 (dq, J = 27.7, 7.7, 6,6 Hz, 4H), 3.85 (t, J = 8.0 Hz, IH), 4.19 (m, 2H), 5.49 (s, IH), 6.61 (q, J = 6.8 Hz, IH), 7.32 (m, 3H), 7,45 (dd, J = 8.6, 2.3 Hz, IH), 7.52 (d, J = 8.1 Hz, IH), 7,67 (d, J = 8.5 Hz, IH)
ex Ή NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz, 4H), 1.54 (m, 4H), 1.76 (dd, J = 13.1, 7.2 Hz, IH), 2.11 (dd, J = 13.1, 8.8 Hz, IH), 2.77 (d, J = 1 1.0 Hz, IH), 2.91 (d, J = 1 1.0 Hz, IH), 3.54 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, IH), 4.19 (qd, J = 7.1, 1.7 Hz, 2H), 5.53 (s, IH), 6.54 (q, J = 6.7 Hz, IH), 7.36 (d, J = 2.2 Hz, IH), 7.53 (dd, J - 8.6, 2.2 Hz, IH), 7.68 (dd, J = 23.2, 8.4 Hz, 2H), 7.84 (s, IH), 7.97 (d, J = 8.1 Hz, IH)
ey Ή NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz, 4H), 1.54 (ddd, J = 11.9, 6.5, 4.3 Hz, 4H), 1.76 (dd, J = 13.1 , 7.2 Hz, IH), 2.11 (dd, J = 13.1, 8.7 Hz, IH), 2.77 (d, J = 1 1.0 Hz, IH), 2.91 (d, J = 1 1.0 Hz, IH), 3.52 (dq, J = 26.9, 7.7, 6.7 Hz, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, IH), 4.19 (qd, J = 7.2, 1.6 Hz, 2H), 5.53 (s, IH), 6.63 (q, J = 6.7 Hz, IH), 7.10 (tt, J = 9.2, 2,4 Hz, IH), 7,19 (s, 2H), 7,34 (d, J = 2.2 Hz, IH), 7.50 (dd, J = 8.6, 2.2 Hz, IH), 7.70 (d, J = 8.5 Hz, IH)
ez ¾ NMR (400 MHz, MeOH-d4): δ ppm 0.07 (d, J = 1.0 Hz, IH), 0.88 (dd, J = 14.3, 7.9 Hz, IH), 1.28 (m, 6H), 1.56 (m, 3H), 1.75 (dd, J = 13.1, 6.7 Hz, IH), 2.07 (dd, J = 13.1, 8,8 Hz, 2H), 2.84 (d, J = 10.5 Hz, IH), 2.96 (d, J = 10.5 Hz, IH), 3.49 (m, 4H), 3.88 (m, IH), 4.20 (m, 2H), 4.56 (s, 2H), 5.44 (d, J = 1.0 Hz, IH), 6.52 (q, J = 6.7 Hz, IH), 7.23 (m, 3H), 7.40 (m, IH), 7.66 (m, 2H)
fa lH NMR (400 MHz, MeOH-d4): δ ppm 1 ,27 (t, J = 7,1 Hz, 3H), 1 ,53 (m, 4H), 1.75 (dd, J = 13.1 , 7.2 Hz, IH), 2.10 (dd, J = 13.1 , 8.8 Hz, IH), 2.76 (d, J = 1 1.0 Hz, IH), 2.90 (d, J = 10.9 Hz, IH), 3.52 (m, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, IH), 4.18 (qd, J = 7.2, 1.6 Hz, 2H), 5.52 (s, IH), 6.60 (q, J = 6.8 Hz, IH), 7.31 (d, J = 2.3 Hz, IH), 7,45 (m, 3H), 7.67 (d, J = 8.5 Hz, IH)
fb *H NMR (400 MHz, MeOH-ifc): δ ppm 0.89 (dd, J = 10.8, 3.8 Hz, IH), 1.27 (t, J = 7.1 Hz, 4H), 1.53 (m, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, IH), 2.10 (dd, J = 13.1 , 8.7 Hz, IH),
2.25 (s, IH), 2.35 (d, J = 3.2 Hz, 6H), 2.77 (d, J = 1 1.0 Hz, IH), 2.91 (d, J = 1 1.0 Hz, IH), 3.50 (m, 4H), 3.85 (dd, J = 8.7, 7.2 Hz, IH), 4.19 (qd, J = 7.2, 1.6 Hz, 2H), 4,87 (d, J = 5,2 Hz, 13H), 5.44 (s, IH), 6.64 (q, J = 6.8 Hz, IH), 7.18 (d, J = 7.7 Hz, 2H),
7.26 (m, 2H), 7.41 (dd, J = 8.5, 2.3 Hz, IH), 7.65 (d, J = 8.5 Hz, IH)
fc JH NMR (400 MHz, MeOH-d4): δ ppm 0.89 (t, J = 6,7 Hz, IH), 1.30 (m, 1 IH), 1.59 (dt, J = 7.7, 4.0 Hz, 9H), 1.94 (dd, J = 13.4, 8.3 Hz, 2H), 2.45 (s, 15H), 2.80 (s, 3H), 3.12 (m, 4H)5 3.55 (tdd, J = 24.1, 17.0, 12.0 Hz, 9H), 4.28 (m, 6H), 5.51 (s, 2H), 6.64 (q, J = 6.8 Hz, 2H), 7.21 (s, 4H), 7.28 (d, J = 2.3 Hz, 2H), 7.44 (dd, J = 8.5, 2.3 Hz, 2H), 7.66 (d, J = 8.6 Hz, 2H)
fd Ή NMR (400 MHz, MeOH-d4): δ ppm 0.08 (dd, J = 4.2, 1.7 Hz, IH), 0.90 (q, J = 7.7 Hz, IH), 1.26 (1, 1 = 7.1 Hz, 4H), 1.50 (dt, J = 33.9, 6.4 Hz, 7H), 1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.10 (dd, J = 13,1, 8.8 Hz, IH), 2.76 (d, J = 11.0 Hz, 1H), 2.91 (d, J = 11.0 Hz, IH), 3.50 (dq, J = 24.8, 7.5, 6.5 Hz, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, IH), 4.19 (ttd, J = 7.1, 4.5, 2.1 Hz, 4H), 5.49 (s, IH), 6.66 (q, J = 6.8 Hz, IH), 7.27 (m, 4H), 7.43 (dd, J = 8.5, 2.3 Hz, IH), 7.65 (d, J = 8.5 Hz, IH)
fe Ή NMR (400 MHz, MeOH-d4): δ ppm .26 (td, J = 7.2, 1.1 Hz, 4H), 1.52 (dt, J = 1 1.8, 5.7 Hz, 4H), 1.74 (dd, J = 13.2, 7.2 Hz, IH), 2.09 (dd, J = 13.2, 8.7 Hz, IH), 2.38 (s, 6H), 2.75 (d, J = 1 1.0 Hz, IH), 2.90 (d, J = 11.0 Hz, IH), 3.50 (m, 5H), 3.82 (t, J = 8.0 Hz, IH), 4.18 (m, 2H), 5.45 (s, IH), 6.66 (q, J = 6.8 Hz, IH), 7.04 (s, 2H), 7.12 (d, J = 1.8 Hz, IH), 7.25 (d, J = 2.1 Hz, IH), 7.41 (m, IH), 7.66 (d, J = 8.5 Hz, IH)
ff ¾ NMR (400 MHz, MeOH-d4): δ ppml.27 (t, J = 7.1 Hz, 3H), 1.54 (m, 4H), 1.76 (dd, J = 13.1, 7.3 Hz, IH), 2.1 1 (dd, J = 13.1 , 8.7 Hz, IH), 2.43 (s, 3H), 2.78 (d, J = 1 1.0 Hz, IH), 2.92 (d, J = 11.0 Hz, IH), 3.52 (m, 4H), 3.86 (dd, J = 8.7, 7.3 Hz, IH), 4.19 (qd, J = 7.1, 1.6 Hz, 2H), 5.50 (s, 1H), 6.61 (q, J = 6.8 Hz, lH), 7.18 (s, IH), 7.31 (m, 2H), 7.39 (s, IH), 7.46 (dd, J = 8.5, 2.3 Hz, IH), 7.68 (m, IH)
fg lH NMR (400 MHz, MeOH-d4): δ ppm 0.89 (t, J = 6.9 Hz, IH), 1.27 (m, 6H), 1.53 (dt, J = 7.9, 4.6 Hz, 4H), 1.76 (dd, J = 13.1, 7.3 Hz, IH), 2.11 (m, IH), 2.35 (d, J = 1.9 Hz, 3H), 2.77 (d, J = 11.0 Hz, IH), 2.91 (d, J = 11.0 Hz, IH), 3.49 (dp, J = 25.1, 5.9 Hz, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, IH), 4.19 (qd, J = 7.1, 1.6 Hz, 2H), 4.87 (s, 13H), 5.49 (s, IH), 6.62 (q, J = 6.8 Hz, IH), 7.26 (m, 4H), 7.43 (dd, J = 8.6, 2.3 Hz, IH), 7,66 (d, J = 8.5 Hz, IH)
fh Ή NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz, 4H), 1.53 (dp, J = 7.3, 3.6, 2.9 Hz, 4H), 1.75 (dd, J = 13.1, 7.3 Hz, IH), 2.10 (dd, J = 13.1, 8.7 Hz, IH), 2.40 (s, 3H), 2.77 (d, J = 11.0 Hz, IH), 2.91 (d, J = 1 1.0 Hz, IH), 3.51 (m, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, lH), 4.19 (qd, J = 7.1 , 1.6 Hz, 2H), 5.50 (s, IH), 6.61 (q, J = 6.7 Hz, IH), 7.30 (d, J = 2.3 Hz, IH), 7.45 (m, 4H), 7.67 (d, J = 8.5 Hz, IH)
fi 'H MR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 5H), 1.53 (m, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, IH), 2.09 (dd, J = 13.1, 8.7 Hz, IH), 2.76 (d, J = 1 1.0 Hz, IH), 2.90 (d, J = 1 1.0 Hz, 1H), 3.51 (dtt, J = 18.9, 13.4, 7.4 Hz, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, IH), 4.18 (qd, J = 7.2, 1.6 Hz, 2H), 5.50 (d, J = 10.3 Hz, IH), 6.58 (q, J = 6.7 Hz, IH), 7.32 (d, J = 2.2 Hz, IH), 7.47 (m, 4H), 7.67 (m, 2H)
fj Ή NMR (400 MHz, MeOH-d4): δ ppm 0.87 (dd, J = 11.5, 4.7 Hz, IH), 1.26 (ddd, J = 1 .3, 6.9, 5.5 Hz, 12H), 1.48 (m, 4H), 1.72 (dd, J = 13.1, 7.3 Hz, IH), 2.05 (m, IH), 2.74 (d, J = 11.0 Hz, IH), 2.93 (m, 2H), 3.45 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, IH), 4, 17 (qd, J = 7, 1, 1.4 Hz, 2H), 5.44 (s, IH), 6.63 (q, J = 6.8 Hz, IH), 7.34 (m, 7H), 7.66 (d, J = 8.5 Hz, IH)
fk Ή NMR (400 MHz, MeOH-d4): δ ppm 0.88 (d, J = 7.9 Hz, IH), 1.19 (s, 2H), 1.26 (t, J = 7.1 Hz, 4H), 1.53 (dt, J = 8.3, 4.9 Hz, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, IH), 2.10 (dd, J = 13.1, 8.8 Hz, IH), 2.76 (d, J = 11.0 Hz, IH), 2.90 (d, J = 10.9 Hz, IH), 3.51 (m, 4H), 3.83 (dd, J = 8.8, 7.2 Hz, IH), 4.18 (qd, J = 7.1, 1.7 Hz, 2H), 4.87 (s, 7H), 5.52 (s, 1H), 6.40 (q, J = 6.6 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1 H), 7.55 (dd, J = 8.5, 2.3 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 8.1 1 (s, 2H)
fl lH NMR (400 MHz, MeOH-d4): δ ppm 1.27 (m, 6H), 1.54 (m, 7H), 1.77 (dd, J =
13.1 , 7.3 Hz, 2H), 2.12 (dd, J = 13.1, 8.7 Hz, 2H), 2.23 (dd, J = 4.4, 1.5 Hz, 3H), 2.36 (d, J = 2, 1 Hz, 5H), 2.79 (d, J = 1 1.1 Hz, 2H), 2.93 (d, J = 1 1.0 Hz, 2H), 3.30 (d, J = 9.7 Hz, 1H), 3.52 (dq, J = 19.4, 6.4 Hz, 7H), 3.88 (dd, J = 8.8, 7.3 Hz, 2H), 4.19 (dddd, J = 8.7, 7.1, 5.6, 1.7 Hz, 3H), 5.49 (q, J - 2.5, 1.9 Hz, 2H), 6.65 (q, J = 6.7 Hz, 2H), 7.22 (m, 6H), 7.43 (m, 3H), 7.67 (d, J = 8.5 Hz, 2H)
fm lH NMR (400 MHz, MeOH-d4): δ ppm 1.30 (m, 5H), 1 ,61 (m, 4H), 1.96 (dd, J = 13.4, 8,4 Hz, 1H), 2.37 (dd, J = 13.4, 8,7 Hz, 1H), 2.81 (s, 1H), 3.13 (q, J = 11.6 Hz, 2H), 3.57 (m, 4H), 4.30 (m, 3H), 5.56 (s, 1H), 6.55 (q, J = 6.7 Hz, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.55 (m, 5H), 7.69 (d, J = 8.5 Hz, 1H)
fn 'H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (m, 4H), 1.53 (m, 4H), 1.75 (dd, J =
13.1, 7.2 Hz, 1H), 2, 10 (dd, J = 13.1, 8.8 Hz, 1H), 2.76 (d, J = 10,9 Hz, 1H), 2.90 (d, J = 1 1.0 Hz, 1H), 3.51 (m, 4H), 3,82 (dd, J = 8.8, 7,2 Hz, 1H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.53 (s, 1H), 6.49 (q, J = 6.7 Hz, 1H), 7,34 (d, J = 2.2 Hz, 1H), 7.52 (m, 2H), 7.68 (d, J = 8.6 Hz, 1H), 7.81 (s, 2H)
fo Ή NMR (400 MHz, MeOH-d4): δ ppml ,27 (t, J = 7.1 Hz, 4H), 1.54 (m, 4H), 1.75 (dd, J = 13.1 , 7.2 Hz, 1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.77 (d, J = 1 1 ,0 Hz, 1H), 2.83 (s, 1H), 2.91 (d, J = 1 1.0 Hz, lH), 3.53 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, 1H), 4,19 (qd, J = 7.2, 1.6 Hz, 2H), 5.53 (s, 1H), 6.53 (q, J = 6.8 Hz, 1H), 7.37 (d, J = 2.2 Hz, 1H), 7.53 (dd, J = 8.5, 2.2 Hz, 1H), 7.62 (ddd, J = 7.9, 5.0, 0.9 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.98 (m, 1H), 8.67 (dd, J = 5,0, 1.6 Hz, 1H), 8,75 (d, J = 2.2 Hz, 1H)fp Ή NMR (400 MHz, MeOH-d4): δ ppml ,31 (m, 10H), 1.54 (m, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2,77 (d, J = 11.0 Hz, 1PI), 2.91 (d, J = 11.0 Hz, 1H), 3.53 (m, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, 1H), 4.19 (qd, J = 7.1, 1.6 Hz, 2H), 4.69 (p, 3 = 6.1 Hz, 1H), 5.51 (s, 1H), 6.72 (q, J = 7.0 Hz, 3H), 6.83 (dt, J = 11.3, 2.3 Hz, 1H), 7.03 (m, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.46 (dd, J = 8.5, 2,3 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H)
fq Ή NMR (400 MHz, MeOH-d4): δ ppm0.88 (m, 1H), 1.37 (m, 22H), 1.75 (dd, J = 13.1, 7.4 Hz, 2H), 2.09 (dd, J = 13.1, 8.8 Hz, 2H), 2.21 (s, 2H), 2.78 (d, J = 1 1.1 Hz, 2H), 2.91 (d, J = 1 1.1 Hz, 2H), 3.49 (m, 8H), 3.88 (dd, J = 8.8, 7.4 Hz, 2H), 4.12 (m, 8H), 5.49 (s, 2H), 6.79 (m, 7H), 7.03 (s, 2H), 7.28 (d, J = 2.3 Hz, 2H), 7.42 (dd, J = 8.6, 2.2 Hz, 2H), 7.67 (d, J - 8.5 Hz, 2H)
fr Ή NMR (400 MHz, MeOH-d4): δ ppml .32 (m, 15H), 1.52 (m, 4H), 1.74 (dd, J = 13.1, 7.2 Hz, 1H), 2.09 (dd, J = 13.1, 8.8 Hz, 1H), 2.32 (d, J = 0.7 Hz, 1H), 2.43 (d, J = 0.8 Hz, 3H), 2,76 (d, J = 11 ,0 Hz, 1H), 2.90 (d, J = 1 1.0 Hz, 1H), 3.48 (m, 4H), 3.83 (dd, J = 8.7, 7,2 Hz, 1H), 4.18 (qd, J = 7,2, 1.5 Hz, 2H), 5.43 (s, 1H), 6.63 (q, J = 6,8 Hz, 1H), 7.06 (s, 1H), 7.26 (m, 2H), 7.34 (q, J = 1 ,3 Hz, 1H), 7.42 (dd, J = 8.5, 2.3 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H)
fs Ή NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.2 Hz, 3H), 1.55 (m, 4H), Ϊ .77 (dd, J = 13.1, 7.3 Hz, 1H), 2.12 (dd, J = 13.2, 8.8 Hz, 1H), 2.79 (d, J = 1 1.0 Hz, 1H), 2.92 (d, J = 1 1.0 Hz, 1H), 3.53 (m, 4H), 3,86 (dd, J = 8.7, 7.3 Hz, 1H), 4.19 (qd, J = 7.1, 1.7 Hz, 2H), 4.86 (s, 3H), 5.53 (s, 1H), 6.57 (q, J = 6.8 Hz, 1H), 7,34 (d, J - 2.2 Hz, 1H), 7.51 (dd, J = 8.5, 2.3 Hz, 1H), 7.72 (m, 2H), 7.84 (m, 2H), 7,92 (s, 1H)ft Ή NMR (400 MHz, MeOH-d4): δ ppm 0.88 (m, 2H), 1.24 (m, 4H), 1.39 (t, J = 7.0 Hz, 3H), 1.50 (q, J = 7.7, 5.2 Hz, 4H), 1.74 (ddd, J = 13.3, 7.3, 1.8 Hz, 1H), 2.08 (ddd} J - 1 1.4, 8.7, 2.6 Hz, 1H); 2.39 (s, 3H), 2.76 (d, J = 11.1 Hz, 1H), 2.88 (dd, J = 11.0, 5.7 Hz, 1H), 3.58 (m, 4H), 3.85 (m, 1H), 4.13 (m, 4H), 5.73 (s, IH), 6.42 (d, J = 2.4 Hz, 1H), 6.70 (dt, J = 10.7, 2.2 Hz, 1H), 6.80 (p, J = 6.5 Hz, 1H), 7.01 (m, 2H), 7.63 (d, J = 1.9 Hz, 1H), 7.76 (m, 2H), 8.00 (d, J - 2.4 Hz, 1H)
fu 1H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J - 7.1 Hz, 4H), 1.50 (dt, J = 9.9, 5.2 Hz, 4H), 1.73 (dd, J = 13,1 , 7.2 Hz, IH), 2,07 (dd, J = 13,1 , 8.7 Hz, 1H), 2.22 (s, 1H), 2.29 (d, J = 10.3 Hz, 6H), 2.39 (s, 3H), 2.75 (d, J = 1 1.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.52 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.74 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.75 (m, 1H), 7. 9 (d, J = 7.9 Hz, 1H), 7.39 (m, 2H), 7.59 (d, J = 1.8 Hz, 1H), 7.72 (m, 2H), 7.96 (d, J = 2.3 Hz, ΪΗ)
fv 'H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (m, 4H), 1.51 (dt, J = 10.6, 5.6 Hz, 4H), 1.74 (dd, J = 13,1 , 7.2 Hz, 1H), 2.08 (dd, J = 13.1, 8.7 Hz, 1H), 2.39 (s, 3H), 2.76 (d, J = 11.0 Hz, 1H), 2.89 (d, J = 1 1.0 Hz, 1H), 3.53 (m, 4H), 3.83 (m, 1H), 4.18 (m, 2H), 4.85 (d, J = 10.8 Hz, 1H), 5.73 (s, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.83 (q, J = 6.6 Hz, 1H), 7.60 (m, 4H), 7.79 (m, 2H), 8.00 (d, J = 2.4 Hz, 1H)
fw 'H NMR (400 MHz, MeOH-d4): δ ppm 1.25 (t, J = 7.1 Hz, 3H), 1.46 (m, 7H), 1.73 (dd, J = 13.1, 7.2 Hz, 1H), 2.06 (dd, J - 13.1, 8.8 Hz, 1H), 2.39 (s, 3H), 2.73 (d, J = 1 1.0 Hz, 1H), 2.87 (d, J = 11.0 Hz, lH), 3.52 (m, 4H), 3.80 (dd, J = 8.7, 7.1 Hz, 1H), 4.16 (m, 4H), 5.73 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.78 (q, J = 6.6 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 7.57 (m, 2H), 7.71 (m, 3H), 7.98 (d, J = 2.4 Hz, 1H)
fx Ή NMR (400 MHz, MeOH-d4): δ ppm 1.26 (m, 4H), 1.39 (t, J = 7,0 Hz, 3H), 1.51 (dt, J = 10.6, 5.6 Hz, 4H), 1.73 (dd, J = 13.1, 7.1 Hz, 1H), 2.07 (dd, J = 13.0, 8.8 Hz, IH), 2.39 (s, 3H), 2.74 (d, J = 10.9 Hz, 1H), 2.88 (d, J = 11 ,0 Hz, 1H), 3.53 (m, 4H), 3,81 (dd, J = 8.8, 7.1 Hz, 1H), 4.13 (m, 4H), 4,87 (s, 13H), 5.74 (s, 1H), 6.41 (d, J = 2,4 Hz, 1H), 6,78 (q, J = 7.6, 7,0 Hz, IH), 6.93 (m, 1H), 7.20 (m, 2H), 7.34 (t, J = 7.9 Hz, 1H), 7.62 (d, J = 1.8 Hz, IH), 7,75 (m, 2H), 7.98 (d, J = 2,4 Hz, 1H)
fy *H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (m, 3H), 1.50 (dt, J = 10.5, 5.8 Hz, 4H), 1.73 (dd, J = 13.1, 7.2 Hz, 1H), 2.07 (dd, J = 13.0, 8.8 Hz, 1H), 2.39 (s, 3H), 2.74 (d, J = 11.0 Hz, 1H), 2.88 (d, J = 1 1.0 Hz, 1H), 3.52 (m, 4H), 3.80 (m, 1H), 4.17 (qd, J = 7.1 , 1.6 Hz, 2H), 5.73 (s, 1H), 6.42 (d, J = 2.3 Hz, 1H), 6.84 (q, J = 6.6 Hz, IH), 6.99 (tt, J = 9,1 , 2.4 Hz, IH), 7.34 (m, 2H), 7.68 (d, J = 1.9 Hz, IH), 7.79 (m, 2H), 8.01 (d, J = 2.4 Hz, IH)
fz *H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (m, 3H), 1.51 (dt, J = 10.6, 5.6 Hz, 4H), 1.73 (dd, J = 13.1, 7.2 Hz, IH), 2.07 (dd, J = 13.1, 8.8 Hz, IH), 2.40 (s, 3H), 2.74 (d, J = 11.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, IH), 3.52 (dq, J = 25.8, 8.1 , 6.9 Hz, 4H), 3.81 (dd, J = 8.8, 7.1 Hz, IH), 4.17 (qd, J = 7.1 , 1.6 Hz, 2H), 5.73 (s, IH), 6.43 (d, J = 2.4 Hz, IH), 6,83 (q, J = 6.6 Hz, IH), 7.69 (m, 3H), 7.82 (m, 2H), 7.98 (m, 3H)ga Ή NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz, 3H), 1.41 (t, J = 7.0 Hz, 3H), 1.53 (m, 4H), 1.75 (dd, J = 13.1, 7.3 Hz, IH), 2.11 (m, IH), 2.77 (d, J = 11 ,0 Hz, IH), 2.91 (d, J = 11.0 Hz, lH), 3.52 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, IH), 4.17 (m, 4H), 5.49 (s, IH), 6.66 (q, J = 6.8 Hz, IH), 7.02 (s, IH), 7.27 (m, 3H), 7.45 (dd, J = 8.5, 2.3 Hz, IH), 7.66 (d, J = 8.5 Hz, IH)
gb Ή NMR (400 MHz, MeOH-d4): δ ppm 0.88 (m, 2H), 1.17 (t, J = 7.0 Hz, IH), 1.31 (m, 12H), 1.51 (dt, J = 11.3, 5,6 Hz, 4H), 1.74 (ddd, J = 13.1, 7.3, 1.9 Hz, 1H), 2.08 (ddd, J = 11.9, 8.8, 2.8 Hz, IH), 2.39 (s, 3H), 2.76 (d, J = 11.0 Hz, IH), 2.89 (dd, J = 11.0, 5.9 Hz, IH), 3.57 (m, 5H), 3.84 (dt, J = 8,6, 7,2 Hz, IH), 4.18 (qd, J = 7.1, 1.7 Hz, IH), 4.64 (p, J - 6.1 Hz, IH), 5.74 (s, IH), 6.41 (d, J = 2.3 Hz, IH), 6.78 (q, J = 6.5 Hz, IH), 7.16 (t, J = 8.6 Hz, IH), 7,44 (m, 2H), 7.61 (d, J = 1.9 Hz, IH), 7.73 (m, 2H), 7.98 (d, J = 2.4 Hz, IH)
gc ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.26 (m, 4H), 1.51 (dt, J = 10.6, 5.7 Hz, 4H), 1.74 (dd, J = 13.1 , 7.2 Hz, IH), 2.07 (dd, J = 13.1, 8.8 Hz, IH), 2.28 (s, IH), 2.37 (d, J = 16.9 Hz, 9H), 2.75 (d, J = 1 1.0 Hz, IH), 2.89 (d, J = 11.0 Hz, I H), 3.53 (dt, J = 22.1, 6.0 Hz, 4H), 3.82 (dd, J - 8.7, 7.2 Hz, IH), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.74 (s, IH), 6.41 (d, J = 2.3 Hz, IH), 6.77 (q, J - 6.6 Hz, IH), 7.03 (m, IH), 7.27 (d, J - 1.5 Hz, 2H), 7.60 (d, J = 1.8 Hz, IH), 7.74 (m, 2H), 7.97 (d, J = 2.4 Hz, IH)
gd *H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (q, J = 7.1, 6.4 Hz, 4H), 1.50 (dt, J = 10.3, 5.6 Hz, 4H), 1 .73 (dd, J = 13.0, 7.2 Hz, IH), 2.07 (dd, J = 13.1, 8.8 Hz, IH), 2.39 (d, J = 3.0 Hz, 6H), 2.74 (d, J = 10.9 Hz, IH), 2.88 (d, J = 10.9 Hz, IH), 3.52 (dt, J = 22.1, 6.1 Hz, 4H), 3.81 (dd, J = 8.8, 7.1 Hz, IH), 4.17 (qd, J = 7.1 , 1.6 Hz, 2H), 4.87 (s, 9H), 5.73 (s, IH), 6,42 (d, J = 2.3 Hz, IH), 6.81 (q, J = 6.6 Hz, IH), 7.23 (s, IH), 7.42 (s, IH), 7.48 (d, J = 2,0 Hz, IH), 7.62 (d, J = 1.9 Hz, IH), 7.71 (dd, J = 8.1 , 1.9 Hz, H), 7.79 (d, J = 8.2 Hz, IH), 8.00 (d, J = 2.4 Hz, IH)
ge !H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (t, J = 7,0 Hz, IH), 1 ,26 (m, 5H), 1.50 (dt, J = 10.5, 5.4 Hz, 4H), 1.73 (dd, J = 13.1, 7.2 Hz, IH), 2.07 (dd, J = 13.1, 8.8 Hz, IH), 2.29 (d, J - 1,9 Hz, 3H), 2.39 (s, 3H), 2.74 (d, J = 10.9 Hz, IH), 2.88 (d, J - 1 1.0 Hz, IH), 3,52 (m, 4H), 3.81 (dd, J = 8.8, 7.2 Hz, IH), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.73 (s, IH), 6.41 (d, J = 2.4 Hz, IH), 6.79 (q, J = 6.6 Hz, IH), 7.37 (m, 3H), 7.63 (d, J = 1.9 Hz, IH), 7.76 (m, 2H), 7.98 (d, J = 2.4 Hz, IH)
gf ¾ NMR (400 MHz, MeOH-d4): δ ppm 0.08 (m, IH), 1.26 (m, 4H), 1.36 (s, 9H), 1.51 (dt, J - 10.5, 5.5 Hz, 5H), 1.74 (dd, J = 13.1, 7.2 Hz, IH), 2.08 (dd, J = 13.1, 8.8 Hz, IH), 2.40 (s, 3H), 2.74 (d, J = 11.0 Hz, IH), 2.89 (d, J = 1 1.0 Hz, IH), 3.53 (dt, J = 23.0, 6.0 Hz, 4H), 3.81 (dd, J = 8.8, 7.1 Hz, IH), 4.17 (qd, J - 7.1, 1.6 Hz, 2H), 5.74 (s, IH), 6.42 (d, J = 2.4 Hz, IH), 6.76 (q, J = 6.6 Hz, IH), 7.43 (m, 3H), 7.61 (d, J = 1.9 Hz, IH), 7.73 (m, 3H), 7.99 (d, J = 2.4 Hz, IH)
gg ¾ NMR (400 MHz, MeOH-d4): δ ppm .26 (t, J = 7.3 Hz, 6H), 1.50 (dt, J = 10.5, 5.6 Hz, 4H), 1.74 (dd, J = 13.1 , 7.2 Hz, IH), 2,08 (dd, J = 13.1, 8.8 Hz, IH), 2.39 (s, 3H), 2,75 (d, J = 1 1.0 Hz, I H), 2.89 (d, J = 1 1.0 Hz, IH), 3,52 (m, 4H), 3.83 (dd, J - 8.7, 7.2 Hz, IH), 4. 8 (qd, J - 7.1 , 1.6 Hz, 2H), 5,73 (s, IH), 6.42 (d, J = 2.4 Hz, IH), 6.82 (q, J = 6.6 Hz, IH), 7.41 (m, 2H), 7.61 (m, 2H), 7.74 (m, 3H), 8.00 (d, J = 2.4 Hz, IH)
gh 'H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7,2 Hz, 3H), 1.51 (dt, J = 10.4, 5.5 Hz, 4H), 1 ,75 (dd, J = 13.1, 7.3 Hz, IH), 2.10 (dd, J = 13.1, 8.8 Hz, IH), 2.39 (s, 3H), 2.84 (m, 2H), 3.52 (ddq, J = 25.3, 13.2, 7.1, 5.7 Hz, 4H), 3.86 (dd, J = 8.8, 7.2 Hz, IH), 4.18 (qd, J = 7.2, 1.6 Hz, 2H), 5.73 (s, IH), 6.42 (d, J - 2.3 Hz, IH), 6.82 (q, J = 6.6 Hz, IH), 7.33 (t, J = 8.8 Hz, IH), 7.63 (m, 2H), 7.73 (dd, J = 8.3, 1 ,9 Hz, IH), 7.82 (m, 2H), 8.00 (d, J - 2.3 Hz, IH)
gi Ή NMR (400 MHz, MeOH-d4): δ ppm 1.28 (m, 4H), 1.53 (dt, J = 10.2, 5.5 Hz, 4H), 1.82 (dd, J = 13.2, 7.7 Hz, 1 H), 2.19 (m, IH), 2.39 (s, 3H), 2.88 (d, J = 11.2 Hz, IH), 2.99 (d, J = 1 1.2 Hz, IH), 3.55 (m, 4H), 4.02 (t, J = 8.2 Hz, IH), 4.22 (qd, J = 7.1, 1.9 Hz, 2H), 5.74 (s, IH), 6.42 (d, J = 2.3 Hz, IH), 6.82 (m, IH), 7.35 (dt, J = 10.4, 8.4 Hz, IH), 7.50 (ddt, J = 7.9, 3.8, 1.8 Hz, IH), 7.72 (m, 4H), 8.00 (d, J = 2.4 Hz, IH) gj 'H NMR (400 MHz, MeOH-d4): δ ppm 1.31 (m, 3H), 1.65 (dt, J = 12.8, 6,2 Hz, 4H), 2.03 (m, IH), 2.43 (m, 4H), 3.27 (s, 2H), 3.65 (m, 4H), 4.31 (qd, J = 7.1, 2.2 Hz, 2H), 4.58 (t, J = 8.8 Hz, IH), 4.85 (m, IH), 6.43 (d, J = 2.5 Hz, IH), 6.89 (q, J = 6.4 Hz, IH), 7,45 (m, IH), 7.72 (d, J = 1.8 Hz, IH), 7.81 (m, 2H), 8.00 (m, 3H)
gk 'H NMR (400 MHz, MeOH-d4): δ ppm 1.32 (t, J = 7.1 Hz, 3H), 1.64 (q, J = 10.3, 8, 1 Hz, 4H), 2.04 (dd, J = 13.6, 8.9 Hz, IH), 2,44 (m, 4H), 2.80 (s, IH), 3.25 (m, 2H), 3.56 (m, IH), 3.70 (d, J = 5,7 Hz, 2H), 4.32 (qd, J = 7.1, 2,5 Hz, 2H), 4,57 (t, J = 8.8 Hz, IH), 6.44 (d, J = 2,4 Hz, IH), 6,90 (q, J = 6.5 Hz, IH), 7.76 (q, J = 1.5, 1.0 Hz, 2H), 7.85 (m, 2H), 7.95 (m, IH), 8.04 (m, 2H)
gl Ή NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 4H), 1.51 (dt, J = 10.3, 5.5 Hz, 4H), 1.74 (dd, J = 13.1, 7.2 Hz, IH), 2.08 (dd, J = 13.1, 8.8 Hz, IH), 2.40 (s, 3H), 2.75 (d, J = 11.0 Hz, IH), 2.89 (d, J = 1 1.0 Hz, IH), 3.52 (m, 4H), 3.83 (dd, J - 8.7, 7.2 Hz, lH), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.73 (s, 1 H), 6.42 (d, J = 2.3 Hz, 1H), 6.82 (q, J = 6.6 Hz, 1H), 7.31 (ddt, J = 8.1, 2.3, 1.1 Hz, 1H), 7.57 (dd, J = 15.9, 7.9 Hz, 2H), 7.74 (m, 4H), 8.01 (d, J = 2.4 Hz, IH)
gm Ή NMR (400 MHz, MeOH-d4): δ ppm 1.30 (d, J = 34.9 Hz, 12H), 1.51 (dt, J = 10.4, 5.7 Hz, 4H), 1.74 (dd, J = 13.1, 7.2 Hz, IH), 2.06 (m, IH), 2.39 (d, J = 3.3 Hz, 6H), 2.74 (d, J = 1 1.0 Hz, 2H), 2.89 (d, J = 1 .0 Hz, IH), 3.53 (m, 5H), 3.81 (dd, J = 8.7, 7.1 Hz, IH), 4.17 (qd, J = 7.2, 1.6 Hz, 2H), 4.87 (s, 3H), 5.73 (s, IH), 6.41 (d, J = 2.4 Hz, IH), 6,75 (q, J - 6.8 Hz, IH), 7.28 (d, J = 9.0 Hz, 2H), 7.46 (t, J = 1.6 Hz, IH), 7.59 (d, J = 1.8 Hz, IH), 7.75 (m, 2H), 7.98 (d, J - 2.3 Hz, IH)
gn !H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 4H), 1.50 (dt, J = 10.8, 5.6 Hz, 4H), 1.73 (dd, J = 13.1 , 7.2 Hz, IH), 2.07 (dd, J = 13.1, 8.8 Hz, IH), 2.41 (d, J = 11.8 Hz, 6H), 2.74 (d, J = 1 1.0 Hz, IH), 2.88 (d, J = 11.0 Hz, IH), 3.52 (dq, J = 24.2, 7.6, 6.3 Hz, 4H), 3.81 (dd, J = 8,7, 7.2 Hz, IH), 4.18 (qd, J = 7.1, 1,6 Hz, 2H), 5.73 (s, IH), 6.41 (d, J = 2.4 Hz, IH), 6,79 (m, IH), 7.45 (m, 2H), 7.63 (dd, J = 7.6, 2.0 Hz, 2H), 7.75 (m, 2H), 7.98 (d, J = 2.4 Hz, IH)
go Ή NMR (400 MHz, MeOH-d4): δ ppm 0.88 (d, J = 7.9 Hz, IH), 1.26 (t, J = 7.1 Hz, 7H), 1.50 (dt, J = 10,5, 5.6 Hz, 8H), 1.74 (dd, J = 13.1, 7.2 Hz, 2H), 2.07 (dd, J = 13.1, 8.8 Hz, 2H), 2.34 (t, J = 0.6 Hz, IH), 2.40 (d, J = 9.3 Hz, 16H), 2,75 (d, J = 11.0 Hz, 2H), 2,89 (d, J = 11.0 Hz, 2H), 3.52 (m, 8H), 3.82 (dd, J = 8,8, 7.2 Hz, 2H), 4.18 (qd, J = 7.1 , 1.6 Hz, 4H), 5.73 (s, 2H), 6.41 (d, J = 2.3 Hz, 2H), 6.79 (q, J = 6.6 Hz, 2H), 7.44 (d, J = 0.9 Hz, 4H), 7.62 (d, J = 1.8 Hz, 2H), 7.74 (m, 4H), 7.98 (d, J = 2.4 Hz, 2H)
gp 'H NMR (400 MHz, MeOH-d4): δ ppm 1 ,27 (q, J = 7.1, 5.7 Hz, 7H), 1.51 (dt, J = 10.7, 5.5 Hz, 4H), 1.74 (dd, J = 13.1, 7.2 Hz, IH), 2.06 (td, J = 15.3, 14.1, 7.4 Hz, IH), 2.32 (d, J = 2, 1 Hz, 3H), 2.39 (s, 2H), 2.75 (d, J = 11.0 Hz, IH), 2.89 (d, J = 1 1.0 Hz, IH), 3.53 (dt, J = 22.2, 6,1 Hz, 4H), 3.83 (dd, J = 8.8, 7.2 Hz, IH), 4.18 (m, 2H), 5.74 (s, IH), 6.41 (d, J = 2.4 Hz, IH), 6.78 (q, J = 6,5 Hz, IH), 7.10 (t, J = 9.0 Hz, IH), 7.56 (m, 3H), 7.74 (m, 2H), 7.98 (d, J = 2.4 Hz, H)
gq Ή NMR (400 MHz, MeOH-d4): δ ppm 0.89 (m, IH), 1.26 (dq, J = 10.3, 5.8, 3.2 Hz, 6H), 1.46 (m, 7H), 1.74 (dd, J = 13.1, 7.2 Hz, IH), 2.09 (m, IH), 2.39 (s, 3H), 2.75 (d, J = 1 1 ,0 Hz, IH), 2.89 (d, J = 11.0 Hz, IH), 3.53 (m, 4H), 3.82 (dd, J = 8,7, 7.2 Hz, IH), 4.16 (m, 4H), 5.74 (s, IH), 6.41 (d, J = 2.3 Hz, IH), 6.78 (q, J = 6.5 Hz, IH), 7.15 (t, J = 8.6 Hz, IH), 7.47 (m, 4H), 7.73 (m, 2H), 7.97 (d, J = 2.3 Hz, IH)gr 1 Ή NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.52 (t, J = 8.0 Hz, 5H), 1.74 (dd, J = 13.1, 7.2 Hz, IH), 2.08 (dd, J = 13.0, 8.7 Hz, IH), 2.40 (s, 3H), 2.75 (d, J = 11.0 Hz, IH), 2.89 (d, J = 10.9 Hz, IH), 3.25 (p, J = 1.7 Hz, IH), 3.53 (m, 5H), 3.81 (dd, J = 8.8, 7.1 Hz, IH), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 4.82 (s, IH), 5.73 (s, IH), 6.00 (m, IH), 6.42 (d, J = 2.4 Hz, IH), 6.85 (d, J = 6.6 Hz, IH), 7.48 (t, J = 1.9 Hz, IH), 7.69 (m, 3H), 7.80 (m, 3H), 8.03 (d, J = 2.4 Hz, IH)
gs ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.26 (m, 10H), 1.50 (dt, J = 10.3, 5.6 Hz, 4H), 1.73 (dd, J = 13.1, 7,2 Hz, 1H), 2.07 (dd, J = 13.1, 8.8 Hz, lH), 2,39 (s, 3H), 2.74 (d, J = 11.0 Hz, IH), 2.93 (m, 2H), 3.52 (m, 5H), 3.82 (dd, J = 8.7, 7.2 Hz, IH), 4.17 (qd, J = 7.1, 1.5 Hz, 2H), 5.74 (s, IH), 6,41 (d, J = 2.3 Hz, IH), 6.78 (q, J = 6.6 Hz, I H), 7.26 (dt, J = 7.6, 1.4 Hz, IH), 7.36 (t, J = 7.7 Hz, IH), 7.47 (m, 2H), 7.61 (d, J = 1.9 Hz, IH), 7.75 (m, 2H), 7.98 (d, J = 2.4 Hz, IH)
gt lH NMR (400 MHz, MeOH-d4): δ ppm 1.26 (m, 4H), 1.51 (dt, J = 1 1.0, 5.6 Hz, 4H), 1.74 (dd, J = 13.1, 7.2 Hz, IH), 2.07 (dd, J - 13.2, 8.8 Hz, IH), 2.40 (s, 2H), 2.75 (d, J = 10.9 Hz, IH), 2.89 (d, J = 1 1.0 Hz, IH), 3.53 (m, 4H), 3.82 (dd, J = 8.8, 7.2 Hz, IH), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.72 (s, IH), 6.00 (m, IH), 6.43 (d, J = 2.4 Hz, IH), 6.84 (q, J = 6.5 Hz, IH), 7.71 (m, 2H), 7.82 (m, 2H), 7.92 (dd, J = 8.4, 2.3 Hz, IH), 8.05 (dd, J = 15.9, 2.3 Hz, 2H)
gu ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.53 (dt, J = 1 1.1, 5.5 Hz, 4H), 1.74 (dd, J = 13, 1 , 7.2 Hz, IH), 2.07 (dd, J = 13.1, 8.8 Hz, IH), 2.40 (s, 3H), 2.75 (d, J = 1 1.0 Hz, IH), 2.89 (d, J = 1 1.0 Hz, IH), 3.53 (dt, J = 22.4, 6.0 Hz, 4H), 3.81 (dd, J = 8.7, 7.1 Hz, IH), 4.18 (qd, J - 7.1, 1.7 Hz, 2H), 5.73 (s, IH), 6.43 (d, J = 2.4 Hz, IH), 6.86 (q, J = 6.6 Hz, IH), 7.81 (m, 5H), 7.97 (m, IH), 8.03 (d, J = 2.4 Hz, IH)
gv Ή NMR (400 MHz, MeOH-d4): δ ppm 0,08 (m, IH), 1.26 (ra, 4H), 1.51 (dt, J = 10.7, 5.5 Hz, 5H)} 1.73 (dd, J = 13.1, 7.2 Hz, IH), 2.06 (m, IH), 2.40 (s, 3H), 2.74 (d, J = 1 1.0 Hz, IH), 2.88 (d, J = 1 1.0 Hz, IH), 3.26 (s, IH), 3.53 (dt, J = 22.3, 6.1 Hz, 5H), 3.81 (dd, J = 8.7, 7.1 Hz, IH), 4.17 (qd, J = 7, 1 , 1.6 Hz, 2H), 5.74 (s, IH), 6.42 (dd, J = 2.4, 0.6 Hz, IH), 6.83 (q, J = 6.6 Hz, IH), 7.57 (dd, J = 8.1, 7.5 Hz, IH), 7.74 (t, J = 1.1 Hz, IH), 7.87 (m, 4H), 8.00 (d, J = 2.4 Hz, IH), 8.19 (m, IH)
gw !H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.52 (dt, J = 10.3, 5.5 Hz, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, IH), 2.09 (dd, J = 13.1 , 8.8 Hz, IH), 2.41 (s, 3H), 2.76 (d, J = 11.0 Hz, IH), 2.90 (d, J = 11.0 Hz, IH), 3.53 (dt, J = 23,4, 6.0 Hz, 4H), 3.83 (dd, J = 8.8, 7.1 Hz, IH), 4.18 (qd, J = 7.2, 1.7 Hz, 2H), 5.72 (s, IH), 6.44 (d, J - 2.4 Hz, IH), 6.87 (q, J = 6.6 Hz, IH), 7.80 (d, J = 1.6 Hz, IH), 7.89 (m, 2H), 8.00 (s, IH), 8.07 (d, J = 2.4 Hz, IH), 8.30 (d, J = 1 ,5 Hz, 2H)
gx lH NMR (400 MHz, MeOH-d4): δ ppm 1.28 (m, 10H), 1.50 (dt, J = 10.2, 5.5 Hz, 4H), 1.73 (dd, J = 13.1, 7.2 Hz, IH), 2.06 (m, IH), 2.39 (s, 3H), 2.74 (d, J = 11.0 Hz, IH), 2.88 (d, J = 10.9 Hz, IH), 3.53 (m, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, IH), 4.17 (qd, J = 7.2, 1.6 Hz, 2H), 4.65 (h, J = 5.9 Hz, IH), 5.73 (s, IH), 6.41 (d, J = 2.3 Hz, IH), 6.78 (q, J = 6.6 Hz, IH), 6.92 (m, IH), 7.19 (m, 2H), 7.33 (t, J = 7.9 Hz, IH), 7.60 (d, J - 1.8 Hz, IH), 7.74 (m, 2H), 7.98 (d, J = 2.3 Hz, IH)
gy Ή NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.2 Hz, 4H), 1.46 (m, 7H), 1.75 (dd, J = 13.1, 7.3 Hz, IH), 2.09 (dd, J = 13.1, 8,8 Hz, IH), 2.39 (s, 3H), 2.76 (d, J = 1 1.0 Hz, IH), 2.90 (d, J = 1 1.0 Hz, IH), 3.52 (dq, J = 24.9, 7.0, 6,0 Hz, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, IH), 4.18 (ttd, J = 7.0, 5.2, 2.5 Hz, 4H), 5.74 (s, IH), 6.41 (d, J = 2.3 Hz, IH), 6.78 (q, J = 6.5 Hz, IH), 7.18 (m, 2H), 7.35 (dd, J = 8.0, 2.1 Hz, IH), 7.62 (d, J = 1.8 Hz, 1 H), 7.74 (m, 2H), 7.99 (d, J = 2.3 Hz, 1H)
gz lH NMR (400 MHz, MeOH-d4): δ ppm 1.29 (m, 9H), .51 (dt, J = 10.4, 5.6 Hz, 4H), 1.73 (dd, J = 13.1, 7.2 Hz, 1H), 2.07 (dd, J = 13.0, 8.7 Hz, 1H), 2.39 (s, 3H), 2.74 (d, J = 1 1.0 Hz, 1H), 2.88 (d, J = 1 1.0 Hz, 1H), 3.53 (m, 4H), 3.81 (dd, J = 8.7, 7.1 Hz, 1H), 4.17 (qd, J = 7.1 , 1.6 Hz, 2H), 4.66 (h, J = 6.1 Hz, 1H), 5.73 (s, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.70 (dt, J = 10.8, 2.2 Hz, 1H), 6.81 (q, J = 6.6 Hz, 1H), 6.99 (m, 2H), 7.62 (d, J = 1.8 Hz, 1H), 7.72 (dd, J = 8.3, 1.9 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 8.00 (d, J = 2.3 Hz, 1H)
ha ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.29 - 1.40 (m, 3 H), 1.55 - 1.76 (m, 4 H), 2.06 (br. s., 1 H), 2.35 - 2.54 (m, 4 H), 3.29 (s, 2 H) 3.50- 3.78 (m, 4H), 3.85 (s, 3H), 4.34 (dd, J=7.03, 2.34 Hz, 2 H)5 4.60 (s, 1 H), 5.96 (s, 1 H), 6.44 (d, J=2.15 Hz, 1 H), 6.81 (d, J=6.44 Hz, 1 H), 7.03 (d,J=8.79 Hz, 2 H), 7.50 - 7.68 (m, 3 H), 7.70 - 7.82 (m, 2 H), 7.97 (d, J=2.15 Hz, 1 H)
hb ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.34 (t, j=7.13 Hz, 3 H), 1.43 (t, J=7.03 Hz, 3 H), 1.63 - 1.82 (m, 4 H), 2.01 - 2.14 (m, 1 H), 2.43 (s, 3 H) 2.46 - 2.57 (m, 1 H), 3.31 (br. s., 2 H), 3.59 - 3.93 (m, 4 H), 4.1 1 (d, J=7.03 Hz, 2 H), 4.26 - 4.41 (m, 2 H), 4.56 - 4.68 (m, 1 H), 6.44 (d, J=2.15 Hz, 1 H), 6.76 - 6.93 (m, 1 H), 7.04 (d, J=8.79 Hz, 2 H), 7.66 (dd, J=5.17, 3.61 Hz, 3 H), 7.72 - 7.85 (m, 2 H), 7.93 - 8.02 (m, 1 H)hc lH NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.2 Hz, 3H), 1.51 (dt, J = 1 1.0, 5.6 Hz, 4H), 1.74 (dd, J = 13.1 , 7.3 Hz, 1F1), 2.09 (dd, j = 13.1, 8.8 Hz, lH), 2.39 (s, 3H), 2.76 (d, J = 1 1.0 Hz, 1H), 2.90 (d, J = 1.0 Hz, 1H), 3.52 (m, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (qd, J = 7.1 , 1.6 Hz, 2H), 4,88 (s, 7H), 5.72 (s, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.84 (q, J = 6.5 Hz, 1H), 7.52 (m, 2H), 7.67 (d, J = 1.9 Hz, 1H), 7.74 (dd, J = 8.3, 1.9 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 8.01 (d, J = 2.4 Hz, 1H)
hd ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.27 (m, 4H), 1.54 (dt, J = 8.1, 4.7 Hz, 4H), 1.76 (dd, J = 13.1, 7.3 Hz, 1H), 2.11 (dd, J = 13.1, 8.8 Hz, 1H), 2.77 (d, J = 10.9 Hz, 1H), 2.91 (d, J = 10.9 Hz, 1H), 3.53 (dq, J = 16.3, 6.7, 6.2 Hz, 4H), 3.65 (s, 3H), 3.83 (dd, J = 8.8, 7.2 Hz, 1H), 4.19 (qd, j = 7.2, 1.6 Hz, 2H), 5.51 (d, J = 18.6 Hz, 1H), 6.49 (dd, J = 6.9, 2.0 Hz, 1H), 6.81 (q, j = 6.8 Hz, 1H), 6.91 (s, 1H), 7.35 (d, J = 2.2 Hz, 1H), 7.51 (dd, J = 8.5, 2.2 Hz, 1 H), 7,70 (d, J = 8.6 Hz, 1H), 7.80 (d, J = 6.8 Hz, 1H)
he ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 4H), 1.51 (dt, J = 10.8, 5.6 Hz, 5H), 1 .74 (dd, j = 13.1, 7.1 Hz, 1H), 2,07 (dd, J = 13.0, 8.7 Hz, 1H), 2.38 (d, J = 9.6 Hz, 6H), 2.74 (d, J = 10.9 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.53 (dt, J = 21.9, 6.3 Hz, 5H), 3.81 (dd, J = 8.7, 7.1 Hz, 1H), 4.18 (qd, J = 7.1, 1.7 Hz, 2H), 4.88 (s, 15H), 5.74 (s, 1H), 6.42 (d, J = 2.4 Hz, 1H), 6.81 (q, J = 6.6 Hz, 1H), 7,33 (m, 1H), 7.58 (m, 1H), 7.66 (t, J = 2.6 Hz, 2H), 7.77 (m, 2H), 7.99 (d, J = 2.4 Hz, 1H)hf Ή NMR (400 MHz, MeOH-d4): δ ppm 0,08 (m, 1H), 1.26 (t, J = 7.1 Hz, 4H), 1.51 (dt, J - 10.6, 5.6 Hz, 4H), 1.76 (dd, j = 13.2, 7.4 Hz, 1H), 2.1 1 (dd, j = 13.2, 8.8 Hz, 1H), 2.39 (s, 7H), 2.79 (d, J = 11.0 Hz, 1H), 2.92 (d, J = 11.1 Hz, 1H), 3,52 (dq, J = 29.5, 7.4, 6.4 Hz, 5H), 3.89 (dd, j = 8,7, 7.4 Hz, 1H), 4.19 (qd, J = 7.2, 1.7 Hz, 2H), 5.73 (s, 1H), 6,42 (d, J = 2.4 Hz, 1H), 6.80 (q, j = 6.6 Hz, 1H), 7.37 (d, j = 7.9 Hz, 1H), 7.51 (dd, J = 7.9, 1.9 Hz, 1H), 7.62 (d, j = 1.9 Hz, 1H), 7.73 (m, 3H), 7.99 (d, j = 2.4 Hz, 1H)
hg 1H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.51 (dt, j = 10.5, 5 Π Hz, 4H), 1.75 (dd, J = 13.1, 7.3 Hz, 1H), 2.10 (dd, J = 13.1, 8.8 Hz, 1H), 2.40 (s, 3H), 2.77 (d, J = 1 1.0 Hz, 1H), 2.91 (d, J = 1 1.0 Hz, IH), 3.53 (m, 4H), 3.85 (dd, J = 8.7, 7.2 Hz, ΪΗ), 4.18 (qd, J = 7.1, 1.7 Hz, 2H), 5.73 (s, IH), 6.43 (d, J = 2.4 Hz, IH), 6.86 (q, J - 6.6 Hz, IH), 7.50 (dd, J = 8.4, 2.1 Hz, IH), 7.79 (m, 6H), 8.04 (d, J = 2.4 Hz, IH)
hh Ή NMR (400 MHz, MeOH-d4): δ ppm 0.93 (m, 2H), 1.36 (m, 1 IH), 1.69 (td, J = 13.3, 6.6 Hz, IH), 2.04 (dd, J = 13.1, 8.8 Hz, IH), 2.39 (s, 3H), 2.72 (d, J = 1 1.0 Hz, I H), 2.86 (d, J = 1 1.0 Hz, IH), 3.50 (m, 4H), 3.80 (t, J - 7.9 Hz, I H), 4.17 (m, 2H), 5,71 (s, IH), 6.42 (d, J = 2.4 Hz, IH), 6.85 (q, J - 6.6 Hz, I H), 7.20 (dt, J = 8.5, 2.1 Hz, IH), 7.39 (dt, J = 9.7, 2,0 Hz, IH), 7.52 (t, 3 = 1.6 Hz, IH), 7.67 (m, 2H), 7.80 (d, J = 8.3 Hz, IH), 8.01 (d, J = 2,3 Hz, IH)
hl *H NMR (400 MHz, MeOH-d4): δ ppm 0.75 (m, 2H), 1.01 (dq, J = 8,4, 2.4 Hz, 2H), 1.19 (s, IH), 1 ,26 (t, J = 7.1 Hz, 4H), 1.52 (m, 4H), 1 .74 (dd, J = 13.1, 7.2 Hz, IH), 2.02 (m, 2H), 2.75 (d, J = 1 1.0 Hz, I H), 2.89 (d, J = 1 1.0 Hz, I H), 3.49 (m, 4H), 3.82 (dd, J = 8.8, 7.2 Hz, IH), 4.18 (qd, J = 7.1 , 1.5 Hz, 2H), 5.44 (s, IH), 6.60 (q, J = 6.9 Hz, IH), 7.20 (m, 4H), 7.41 (m, 2H), 7.66 (d, J - 8.5 Hz, IH)
hj Ή NMR (400 MHz, MeOH-d4): 6 ppm 1.25 (t, J = 7.1 Hz, 3H), 1.35 (d, J = 6.0 Hz, 6H), 1.49 (ddd, J = 12.1 , 7.6, 4.8 Hz, 4H), 1.72 (dd, J = 13.1, 7.2 Hz, IH), 2.05 (dd, J = 13.1, 8.8 Hz, IH), 2.39 (s, 3H), 2.72 (d, J = 1 1.0 Hz, 3H), 2.87 (d, J = 1 1.0 Hz, I H), 3.51 (m, 4H), 3.80 (dd, J = 8.7, 7.1 Hz, IH), 4.17 (qd, J = 7.1 , 1.6 Hz, 2H), 4.67 (hept, J = 6.1 Hz, IH), 5.73 (s, IH), 6.41 (d, J = 2.4 Hz, IH), 6.78 (q, J = 6.6 Hz, IH), 7.12 (d, J = 8,6 Hz, IH), 7.54 (m, 2H), 7.67 (m, 2H), 7.75 (d, J = 8.3 Hz, IH), 7.98 (d, J = 2.4 Hz, IH)
hk Ή NMR (400 MHz, MeOH-d4): δ ppm 1.27 (m, 4H), 1.54 (m, 4H), 1.75 (dd, J =
13.1 , 7.2 Hz, IH), 2.11 (dd, J = 13.1 , 8,8 Hz, IH), 2.77 (d, J = 1 1.0 Hz, IH), 2.91 (d, J = 1 1.0 Hz, IH), 3.52 (dq, J = 27.4, 7.7, 6.5 Hz, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, I H), 4.19 (qd, J = 7.1 , 1.6 Hz, 2H), 5.51 (d, J = 14.8 Hz, 2H), 6.79 (q, J = 6.8 Hz, IH), 7 ,40 (d, J = 2.2 Hz, IH), 7.52 (m, 2H), 7.73 (d, J = 8.5 Hz, IH), 8.23 (d, J = 8.3 Hz, I H), 8.47 (s, IH), 9.34 (s, I H)
hl 'H NMR (400 MHz, MeOH~d4): δ ppm 1.25 (t, J = 7.1 Hz, 3H), 1.50 (dt, J = 7.8, 4.8 Hz, 4H), 1.73 (dd, J = 13.1, 7.2 Hz, IH), 2.07 (dd, J = 13.1 , 8.7 Hz, IH), 2.74 (d, J = 10.9 Hz, IH), 2.88 (d, J = 10.9 Hz, IH), 3.10 (s, 6H), 3.49 (m, 4H), 3.81 (dd, J = 8.7, 7.2 Hz, IH), 4.17 (qd, J = 7.1 , 1.3 Hz, 2H), 5.47 (s, IH), 6.69 (m, 3H), 7.32 (d, J = 2.2 Hz, IH), 7.45 (dd, J = 8.5, 2.2 Hz, IH), 7.68 (d, J = 8.5 Hz, IH), 8.18 (d, J = 5.2 Hz, IH)
hm ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.24 (t, J = 7.1 Hz, 3H), 1.45 (dt, J = 9.4, 5 ,7 Hz, 4H), 1.70 (dd, J = 13.1, 7.2 Hz, 1H), 2.03 (dd, J = 13.1 , 8.7 Hz, 1H), 2.70 (d, J = 1 1.0 Hz, 1H), 2.85 (d, J = 11.0 Hz, IH), 3.40 (m, 4H), 3.79 (t, J = 7.9 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 5.45 (d, J = 17.0 Hz, IH), 6.68 (q, J = 6.8 Hz, IH), 7.37 (d, J = 2.3 Hz, IH), 7,44 (dd, J = 8.6, 2.2 Hz, IH), 7.56 (m, 3H), 7.71 (d, J = 8.5 Hz, IH), 7.94 (m, 4H)
hn Ή NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz, 3H), 1.36 (s, 9H), 1.52 (m, 4H), 1.77 (dd, J = 13.1 , 7.4 Hz, IH), 2.13 (dd, J = 13.1 , 8.7 Hz, IH), 2.80 (d, J = 1 1.1 Hz, IH), 2.93 (d, J = 1 1.1 Hz, IH), 3.48 (m, 4H), 3.91 (dd, J = 8.7, 7.4 Hz, IH), 4.20 (qd, J = 7.2, 1.7 Hz, 2H), 5.41 (s, IH), 6.64 (q, J - 6.9 Hz, IH), 7.27 (m, 2H), 7.44 (m, 5H), 7.69 (d, J = 7.3 Hz, IH)
ho ]H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (td, J = 7.1 , 2.3 Hz, 3H), 1.53 (dt, J = 13.2, 6.2 Hz, 4H), 1.74 (dt, J = 13.6, 7.0 Hz, IH), 2.09 (m, IH), 2.75 (dd, J = 10.9, 7.2 Hz, IH), 2.90 (dd, J = 11.0, 6.6 Hz, IH), 3.29 (s, IH), 3.52 (m, 4H), 3.83 (td, J = 8.2, 4.3 Hz, IH), 4.18 (q, J = 7.1 Hz, 2H), 5.47 (m, IH), 6.43 (dt, J = 1 1.2, 5.6 Hz, IH), 7.22 (m, IH), 7.38 (m, 2H), 7.61 (dd, J = 5.0, 2,2 Hz, IH), 7.81 (m, 3H)
63hp Ή NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz, 4H), 1.51 (dt, J = 10.0, 5.2 Hz, 4H), 1.80 (in, IH), 2.17 (dd, J = 13.3, 8.8 Hz, IH), 2.86 (d, J - 1 1.2 Hz, IH), 2.97 (d, J = 11.2 Hz, lH), 3.50 (m, 4H), 4.01 (t, J = 8.2 Hz, IH), 4.21 (qd, J = 7.1 , 1.9 Hz, 2H)} 5.63 (s, IH), 6.69 (q, J = 6.6 Hz, IH), 7.30 (ddd, J = 7.9, 6.9, 0.9 Hz, ί H), 7.46 (m, 2H), 7.75 (m, 4H), 8.39 (d, J = 1.0 Hz, IH)
63hq Ή NMR (400 MHz, MeOH-d4): δ ppm 1.28 (t, J = 7.1 Hz, 3H), 1.36 (dd, J = 6.9, 3.7 Hz, 6H), 1.50 (m, 2H), 1.73 (dd, J = 13.1, 6.7 Hz, IH), 2.05 (dd, J = 13.1, 8.8 Hz, IH), 2.81 (d, J = 10.5 Hz, IH), 2.94 (d, J = 10.5 Hz, IH), 3.14 (p, J = 6.9 Hz, IH), 3.47 (dt, J - 12.2, 5.6 Hz, 4H), 3.85 (dd, J = 8.8, 6.7 Hz, IH), 4.19 (q, J = 7.1 Hz, 2H), 4.34 (s, 2H), 5.42 (s, IH), 6.53 (q, J = 6.7 Hz, IH), 7.25 (m, 3H), 7.42 (dd, J = 8.5, 2.2 Hz, IH), 7.68 (d, J = 8.5 Hz, IH), 8.65 (dd, J = 5.0, 0.8 Hz, IH)
631ii- lH NMR (400 MHz, MeOH-d4); δ ppm 1.27 (t, J = 7.1 Hz, 3H), 1.53 (m, 4H), 1.76 (dd, J = 13.1, 7.3 Hz, IH), 2.11 (dd, J = 13.1, 8.7 Hz, IH), 2.77 (d, J = 11.0 Hz, IH), 2.91 (d, J = 11.0 Hz, IH), 3.51 (dq, J = 17.7, 6.1 Hz, 4H), 3.84 (dd, J = 8.7, 7.3 Hz, IH), 4.19 (qd, J = 7.1, 1.6 Hz, 2H), 5.50 (s, IH), 6.60 (q, J = 6.7 Hz, IH), 7.28 (m, 3H), 7.48 (ddd, J = 25.4, 8.2, 3.7 Hz, 3H), 7.66 (d, J = 8.5 Hz, IH)
63hs Ή NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.52 (m, 4H), 1.75 (dd, J = 13.1 , 7.3 Hz, IH), 2.10 (dd, J = 13.1, 8.8 Hz, IH), 2.77 (d, J = 11.0 Hz, IH), 2.91 (d, J = 1 1.0 Hz, IH), 3.50 (dq, J = 25.8, 7.7, 6.9 Hz, 4H), 3.85 (dd, J = 8.7, 7.3 Hz, IH), 4.19 (qd, J = 7.1, 1.5 Hz, 2H), 5.50 (s, IH), 6.60 (q, J = 6.7 Hz, IH), 7.28 (d, J = 2.2 Hz, IH), 7.52 (m, 6H)
63 t 'H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (t, J = 7.1 Hz, 3H), 1.56 (dt, J = 11.3, 5.3 Hz, 4H), 1.86 (dd, J = 13.3, 7.9 Hz, IH), 2.25 (dd, J = 13.3, 8.7 Hz, IH), 2.44 (s, 3H), 2.96 (d, J = 1 1.4 Hz, IH), 3.05 (d, J = 11.3 Hz, IH), 3.54 (m, 3H), 3.75 (s, I H), 4.13 (t, J = 8.3 Hz, IH), 4.24 (qd, J = 7.2, 2.0 Hz, 2H), 5.48 (s, IH), 6,64 (q, J = 6.8 Hz, IH), 7.26 (d, J = 2.3 Hz, IH), 7.35 (s, 4H), 7.42 (dd, J = 8.5, 2.3 Hz, IH), 7.65 (d, J = 8.5 Hz, IH)
63hu ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.24 (m, 3H), 1.49 (dt, J = 10.2, 5.7 Hz, 4H), 1.72 (m, IH), 2.04 (m, IH), 2.41 (s, 2H), 2.72 (d, J = 10.9 Hz, IH), 2.86 (d, J = 10.9 Hz, IH), 3.52 (m, 4H), 3.79 (dd, J = 8.8, 7.1 Hz, IH), 4.16 (qd, J = 7.1, 1.6 Hz, 2H), 5.76 (s, IH), 6.43 (d, J = 2.4 Hz, IH), 6.82 (q, J = 6.7 Hz, IH), 7.49 (m, 2H), 7.84 (m, 7H), 8.01 (d, J = 2.4 Hz, IH), 8.14 (d, J = 1.9 Hz, IH)
63hv Ή NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.53 (m, 4H), 1.78 (m, 5H), 2.11 (m, 2H), 2.25 (dt, J = 7.9, 4.0 Hz, 2H), 2.41 (d, J = 18,1 Hz, IH), 2.76 (d, J = 1.0 Hz, IH), 2.90 (d, J = 1 1.0 Hz, IH), 3.50 (dq, J = 24.8, 7.6, 6.8 Hz, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, IH), 4.18 (qd, J = 7.1, 1.5 Hz, 2H), 5.48 (s, IH), 5.76 (h, J = 2.0 Hz, IH), 6.93 (q, J = 6.9 Hz, IH), 7.15 (d, J = 2.3 Hz, IH), 7.30 (dd, J = 8.5, 2.3 Hz, IH), 7.58 (d, J = 8.5 Hz, H)
63hw ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz, 3H), 1.52 (dt, J = 8.9, 5.7 Hz, 4H), 1.81 (dd, J = 13.3, 7.7 Hz, IH), 2.17 (dd, J = 13.3, 8.8 Hz, lH), 2.39 (s, 3H), 2.88 (d, J = 1 1.3 Hz, IH), 2.98 (d, J = 11.3 Hz, 1H), 3.53 (m, 4H), 4.04 (t, J = 8.2 Hz, IH), 4.21 (qd, J = 7.2, 1.8 Hz, 2H), 4.90 (d, J = 1.1 Hz, 5H), 5.74 (s, IH), 6.41 (d, J = 2.3 Hz, IH), 6.78 (q, J = 6.6 Hz, IH), 7.17 (t, J = 8.6 Hz, IH), 7.40 (m, 7H), 7.62 (m, 2H), 7.74 (d, J = 8.2 Hz, IH), 7.96 (d, J = 2.3 Hz, IH)
hx Ή NMR (400 MHz, MeOH-d4): δ ppm 1.32 (m, 9H), 1.55 (dt, J = 10.7, 5.8 Hz, 4H), 1.87 (dd, J = 13.3, 8.0 Hz, IH), 2.24 (m, 4H), 2.39 (s, 3H), 2.98 (d, J = 11.4 Hz, IH), 3.06 (d, J = 1 1.4 Hz, IH), 3.58 (m, 4H), 4.22 (m, 3H), 4.63 (p, J = 6.0 Hz, IH), 5.76 (s, IH), 6.41 (d, J - 2.3 Hz, IH), 6.75 (q, J = 6.6 Hz, IH), 6.97 (d, J = 8.2 Hz, IH), 7.45 (d, J = 8.1 Hz, 2H), 7.58 (d, J - 1.7 Hz, IH), 7.71 (m, 2H), 7.96 (d, J = 2.3 Hz, IH)
hy ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.04 (m, 7H), 1.26 (t, J = 7.1 Hz, 4H), 1.52 (m, 4H), 1.74 (dd, J = 13.1, 7.3 Hz, IH), 2.08 (m, 2H), 2.75 (d, J = 11.0 Hz, IH), 2.90 (d, J = 1 1.0 Hz, IH), 3.50 (m, 4H), 3.80 (m, 3H), 4.18 (qd, J = 7.1, 1.4 Hz, 2H), 5.48 (s, IH), 6.70 (q, J = 6.9 Hz, IH), 7.02 (m, 2H), 7.19 (s, 2H), 7.28 (d, J - 2.3 Hz, IH), 7.42 (m, 2H), 7.66 (d, J = 8.5 Hz, IH)
hz ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.33 (t, J = 6.3 Hz, 9H), 1.68 (m, 4H), 2.04 (m, IH), 2.50 (dd, J = 13.6, 8.7 Hz, IH), 3.28 (s, 2H), 3.56 (m, 5H), 4.32 (qd, J = 7.2, 2,2 Hz, 2H), 4,62 (m, 2H), 6.59 (m, IH), 6,97 (m, 2H), 7.53 (m, 9H), 7.66 (dd, J = 8.3, 2.0 Hz, IH), 7,75 (d, J = 8.4 Hz, IH)
ia Ή NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.52 (dt, J = 9.7, 5,5 Hz, 4H), 1.74 (dd, J = 13,0, 7,3 Hz, IH), 2.09 (dd, J = 13,1, 8,8 Hz, IH), 2.75 (d, J = 11.0 Hz, IH), 2.89 (d, J = 11.0 Hz, IH), 3,51 (dq, J = 23.9, 7.7, 6.6 Hz, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, IH), 4.18 (qd, J = 7.1, 1.5 Hz, 2H), 5.56 (s, IH), 6.68 (q, J - 7.2 Hz, IH), 7.67 (d, J = 8.1 Hz, 2H), 7.82 (m, 2H), 8.03 (dd, J = 8.9, 2.0 Hz, IH), 8.15 (m, 3H), 8.81 (dd, J = 2.9, 0.9 Hz, IH)
ib [H NMR (400 MHz, MeOH-d4): δ ppm 1 ,06 (t, J = 7.4 Hz, 3H), 1.24 (m, 3H), 1.50 (dt, J = 10.7, 5.6 Hz, 4H), 1.79 (m, 3H), 2.07 (dd, J = 13.1 , 8.8 Hz, IH), 2.39 (s, 3H), 2.74 (d, J = 10.9 Hz, IH), 2.87 (m, H), 3.55 (m, 5H), 3.81 (dd, J = 8.8, 7.2 Hz, IH), 4.04 (t, J = 6.4 Hz, 2H), 4.17 (qd, J = 7.2, 1.7 Hz, 2H), 5.75 (s, IH), 6,41 (d, J = 2.4 Hz, IH), 6,78 (q, J - 6.6 Hz, IH), 7.15 (t, J = 8.6 Hz, IH), 7.45 (m, 2H), 7,60 (d, J = 1,8 Hz, IH), 7,73 (m, 2H), 7.98 (d, J = 2.4 Hz, IH)
ic ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.00 (t, J = 7.4 Hz, 3H), 1.26 (t, J - 7,1 Hz, 3H), 1.51 (m, 6H), 1.76 (m, 3H), 2.07 (dd, J = 13.1, 8.8 Hz, IH), 2.39 (s, 3H), 2.74 (d, J = 11.0 Hz, IH), 2.88 (d, J = 11.0 Hz, H), 3.53 (qd, J = 13.9, 7.7 Hz, 4H), 3,81 (dd, J = 8.7, 7.2 Hz, IH), 4.14 (m, 4H), 5.74 (s, IH), 6.41 (d, J = 2.3 Hz, IH), 6.78 (q, J = 6.6 Hz, IH), 7.15 (m, IH), 7.46 (m, 2H), 7.61 (d, J = 1.7 Hz, IH), 7.73 (m, 2H), 7.98 (d, J = 2.4 Hz, IH)
id Ή NMR (400 MHz, MeOH-d4); δ ppm 1.25 (t, J = 7.1 Hz, 3H), 1.51 (m, 4H), 1.73 (dd, J = 13.1, 7,2 Hz, IH), 2.07 (dd, J = 13.0, 8.8 Hz, IH), 2.40 (s, 3H), 2.64 (s, 3H), 2,74 (d, J - 11.0 Hz, IH), 2.88 (d, J = 11.0 Hz, IH), 3.52 (m, 4H), 3.81 (dd, J = 8.7, 7.2 Hz, IH), 4.17 (qd, J = 7.1, 1.6 Hz, 2H), 5.74 (s, IH), 6.44 (d, J = 2.3 Hz, IH), 6.86 (q, J = 6.6 Hz, IH), 7.76 (m, 3H), 7.85 (d, J = 1.2 Hz, 2H), 8.08 (m, 2H)
ie !H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (d, J = 6.7 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H), 1.53 (m, 4H), 1.72 (ddd, J = 23.9, 13.2, 7.0 Hz, IH), 1.94 (m, 4H), 2.11 (dd, J = 13.1, 8.8 Hz, IH), 2.77 (d, J = 10.9 Hz, IH), 2.91 (d, J = 1 1.0 Hz, IH), 3.55 (m, 9H), 3.85 (dd, J = 8.7, 7.3 Hz, IH), 4.19 (qd, J = 7.1, 1.7 Hz, 2H), 5.53 (s, IH), 6.69 (q, J = 6.7 Hz, IH), 7.31 (d, J = 2.2 Hz, IH), 7.48 (m, 2H), 7.64 (m, 3H), 7.93 (s, IH) if Ή NMR (400 MHz, MeOH-d4): δ ppm 1.27 (td, J = 7.1, 0.8 Hz, 4H), 1.53 (m, 4H), 1.76 (m, 9H), 1.97 (dd, J = 13.4, 6.8 Hz, 2H), 2.11 (dd, J = 13.1, 8.8 Hz, IH), 2.77 (d, J = 1 1.0 Hz, IH), 2.91 (d, J = 10.9 Hz, IH), 3.31 (m, 3H), 3.51 (dq, J = 19.6, 6.3 Hz, 4H), 3.84 (dd, J = 8.7, 7.3 Hz, IH), 4.19 (m, 2H), 5.48 (s, IH), 6.71 (q, J = 6.9 Hz, IH), 6.94 (d, J = 7.6 Hz, IH), 7.02 (dd, J = 8.4, 2.6 Hz, IH), 7.18 (s, IH), 7.28 (d, J = 2.2 Hz, IH), 7.43 (m, 2H), 7.66 (d, J = 8.5 Hz, IH)
ig !H NMR (400 MHz, MeOH-d4): δ ppm 0.89 (dd, J = 6.7, 0.7 Hz, IH), 1.27 (td, J = 7.1, 0.7 Hz, 3H), 1.53 (m, 4H), 1.75 (dd, J = 13.1 , 7.3 Hz, IH), 2.1 (m, IH), 2.76 (d, J = 11.0 Hz, IH), 2.90 (d, J = 11.0 Hz, IH), 3.30 (dq, J = 3.5, 1.8 Hz, 5H), 3.54 (m, 10H), 3,82 (m, 5H), 4.18 (qd, J = 7.2, 1,6 Hz, 2H), 5.53 (s, IH), 6.70 (q, J = 6.7 Hz, IH), 6,84 (m, IH), 7.30 (m, IH), 7.51 (m, 3H), 7.66 (m, 2H), 7.79 (s, IH)
ih 'H NMR (400 MHz, MeOH-d4): δ ppm 1.39 (m, 12H), 1.84 (dd, J = 13.2, 7.8 Hz, IH), 1.98 (m, 5I-I), 2.24 (m, IH), 2.92 (d, J = 1 1.3 Hz, IH), 3,02 (d, J = 11.2 Hz, IH), 3.54 (ddq, J = 27.6, 15.0, 7,8, 7,4 Hz, 6H), 3,89 (s, IH), 4.07 (t, J = 8.2 Hz, IH), 4.23 (qd, J = 7.1, 2.0 Hz, 2H), 4.93 (d, J = 1.4 Hz, 1 IH), 5.55 (s, IH), 6,63 (q, J = 6,7 Hz, IH), 7.30 (d, J = 2.2 Hz, IH), 7.46 (dd, J = 8.5, 2,3 Hz, IH), 7.63 (m, 3H), 7.89 (dt, J = 7.7, 1.6 Hz, IH), 8,35 (s, IH)
ii Ή NMR (400 MHz, MeOH-d4): δ ppm 1 ,27 (td, J = 7.4, 5.4 Hz, 7H), 1.52 (dt, J = 7.6, 4.7 Hz, 4H), 1.74 (dd, J = 13.1, 7.2 Hz, IH), 2.09 (dd, J = 13.1, 8.7 Hz, IH), 2.74 (m, 3H), 2,90 (d, J = 11.0 Hz, IH), 3.30 (d, J = 9,9 Hz, IH), 3,49 (m, 4H), 3.83 (dd, J = 8,7, 7,2 Hz, IH), 4.18 (qd, J = 7.1, 1.5 Hz, 2H), 5.46 (s, IH), 6.64 (q, J = 6.8 Hz, IH), 7.30 (m, 4H), 7.43 (m, 2H), 7.67 (d, J = 8.5 Hz, IH)
ij ]H NMR (400 MHz, MeOH-d4): 6 ppm 1.30 (dd, J = 6.9, 5.1 Hz, 6H), 1.59 (d, J = 5.6 Hz, 4H), 2.03 (dd, J = 13.4, 7.2 Hz, IH), 2.30 (dd, J = 13.4, 9.2 Hz, IH), 3.03 (m, 2H), 3.22 (d, J = 11.7 Hz, IH), 3.46 (tt, J = 16.4, 7.0 Hz, 2H), 3.62 (q, J = 8.5 Hz, 2H), 4.05 (dd, J = 9.1, 7.1 Hz, IH), 5.48 (s, IH), 6.62 (q, J = 6.7 Hz, IH), 7.31 (m, 4H), 7.44 (m, 2H), 7.66 (d, J = 8.5 Hz, IH)
ik ]H NMR (400 MHz, MeOH-d4): δ ppm 1.05 (i, J = 7.4 Hz, 3H), 1.26 (td, J = 7,2, 0.6 Hz, 4H), 1.51 (dt, J = 10.0, 5.7 Hz, 4H), 1.77 (ddd, J = 27.5, 13.6, 7.1 Hz, 3H), 2,08 (dd, J = 13.1, 8.7 Hz, IH), 2.74 (d, J = 11.0 Hz, IH), 2.88 (d, J = 1 1.0 Hz, IH), 3.30 (p, J = 1.6 Hz, 5H), 3.51 (m, 4H), 3,81 (dd, J = 8.7, 7.2 Hz, IH), 3.95 (t, J = 6.5 Hz, 2H), 4.18 (qd, J = 7.1, 1 ,5 Hz, 2H), 5.53 (s, IH), 6.61 (q, J = 7.2 Hz, IH), 6.97 (m, 2H), 7.56 (m, 6H)
il JH NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 4H), 1.46 (m, 8H), 1.73 (dd, J = 13.0, 7.3 Hz, IH), 2.08 (m, IH), 2.74 (d, J = 1 1.0 Hz, IH), 2.89 (d, J = 11.0 Hz, IH), 3.02 (m, 2H), 3.50 (dd, J = 17.6, 11.2 Hz, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, IH), 4.18 (qd, J = 7.2, 1.5 Hz, 2H), 5.53 (s, IH), 6.99 (q, J = 6,9 Hz, IH), 7.67 (m, 3H), 8,03 (dd, J = 8.9, 2.1 Hz, III), 8.14 (m, 3H), 8.80 (dd, J = 2.8, 0.9 Hz, IH)
im ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 5H), 1.53 (td, J = 7.3, 6.9, 4.5 Hz, 4H), 1.75 (dd, J = 13.1, 7.3 Hz, IH), 2.10 (m, IH), 2.29 (s, 3H), 2.39 (s, 3H), 2,53 (s, 2H), 2.76 (d, J = 11 ,0 Hz, IH), 2,90 (d, J = 11.0 Hz, 1H), 3.52 (m, 6H), 3.83 (m, 3H), 4.18 (qd, J = 7.1, 1.7 Hz, 2H), 5.51 (d, J = 15.3 Hz, IH), 6.71 (q, J = 6.6 Hz, IH), 7.32 (d, J = 2.3 Hz, IH), 7.50 (m, 3H), 7,66 (m, 2H), 7.80 (s, IH)
in lH NMR (400 MHz, MeOH-d4): δ ppm 1.25 (m, 4H), 1.54 (m, 4H), 1.75 (dd, J = 13.1, 7.3 Hz, H), 2, 10 (dd, J = 12,8, 8.5 Hz, IH), 2.66 (s, 3H), 2.76 (d, J = 11.0 Hz, IH), 2.90 (d, J = 11.0 Hz, IH), 3.52 (dd, J = 14.8, 8.9 Hz, 5H), 3.83 (dd, J = 8.7, 7.3 Hz, 1H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.54 (s, 1H), 6.85 (t, J = 7.0 Hz, 1H), 7.65 (d, J = 2.9 Hz, 3H), 8.04 (dd, J = 8.9, 2.0 Hz, 1H), 8.15 (m, 3H), 8.81 (d, J = 2.8 Hz, 1H)io Ή NMR (400 MHz, MeOH-d4): δ ppm 1.15 (t, J = 7.0 Hz, 311), 1.26 (t, J = 7.1 Hz, 6H), 1.53 (dt, J = 10.1, 5.5 Hz, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, 1H), 2.10 (dd, J = 13.1, 8.7 Hz, 1H), 2.76 (d, J = 11.0 Hz, 1H), 2.90 (d, J = 11.0 Hz, 1H), 3.36 (d, J = 7.7 Hz, 1H), 3.54 (m, 6H), 3.83 (dd, J = 8.7, 7.2 Hz, 1H), 4.18 (qd, J = 7.2, 1.6 Hz, 2H), 5.55 (s, 1H), 6.65 (q, J = 7.1 Hz, 1H), 7.46 (m, 2H), 7.62 (d, J - 8.1 Hz, 2H), 7.72 (m, 4H)ίρ JH NMR (400 MHz, MeOH-d4): δ ppm 1.26 (td, J = 7.1, 1.0 Hz, 7H), 1.53 (m, 8H), 1.74 (dd, J = 13.1, 7.2 Hz, 2H), 2.09 (dd, J = 13.1, 8.7 Hz, 2H), 2.75 (d, J = 11.0 Hz, 2H), 2.89 (d, J = 11.0 Hz, 2H), 3.28 (d, J = 14.7 Hz, 1H), 3.53 (m, 9H), 3.82 (dd, J = 8.7, 7.2 Hz, 2H), 4.18 (qd, J = 7.1 , 1.5 Hz, 4H), 5.55 (s, 2H), 6.66 (q, J = 7, 1 Hz, 2H), 7.62 (d, J = 8.1 Hz, 4H), 7.72 (m, 8H), 7.95 (m, 4H)
iq Ή NMR (400 MHz, MeOH-d4): δ ppm 1.27 (m, 6H), 1.54 (m, 4H), 1.78 (dd, J = 13.1 , 7.4 Hz, 1H), 2.14 (dd, J = 13.2, 8.8 Hz, 1H), 2.81 (d, J = 13.9 Hz, 4H), 2.94 (d, J = 1 1.0 Hz, 1H), 3.22 (s, 2H), 3.52 (ddt, J = 19.7, 11.9, 6.0 Hz, 4H), 3.92 (t, J = 8.0 Hz, 1H), 4.21 (qd, J = 7.8, 6.4, 4.7 Hz, 2H), 4.88 (s, III), 5.51 (s, IH), 6.75 (q, J = 6.7 Hz, 1H), 7.49 (m, 2H), 7.72 (m, 2H)
ir lH NMR (400 MHz, MeOH-d4): δ ppm 1.04 (t, J = 7.4 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.51 (m, 4H), 1.76 (ddd, J = 25.2, 13.5, 7.1 Hz, 3H), 2.08 (dd, J = 13.1, 8.8 Hz, 1H), 2.74 (d, J - 11.0 Hz, 1H), 2.89 (d, J = 11.0 Hz, 1H), 3.47 (dq, J = 26.7, 7.9, 6.9 Hz, 4H), 3.82 (dd, J = 8.7, 7.2 Hz, 1H), 3.95 (t, J = 6.5 Hz, 2H), 4.18 (m, 2H), 5.45 (s, 1H), 6.66 (q, J = 6.9 Hz, 1H), 6.97 (m, 2H), 7.55 (m, 9H), 7.73 (d, J = 8.3 Hz, 1H)is ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.28 (t, J = 7.1 Hz, 4H), 1.54 (m, 4H), 1.81 (dd, J = 13.2, 7.6 Hz, 1H), 2.18 (dd, J = 13.3, 8.8 Hz, IH), 2.87 (d, J = 11.2 Hz, 1H), 2.98 (d, J = 1 1.1 Hz, 1H), 3.51 (m, 4H), 4.00 (t, J = 8.1 Hz, 1H), 4.21 (qd, J = 7.1, 1.8 Hz, 2H), 5.49 (d, J = 2.0 Hz, 1H), 6.82 (q, J = 6.7 Hz, 1H), 7.13 (m, 2H), 7.46 (m, 2H), 7.67 (d, J = 8.5 Hz, 1H)
it Ή NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.53 (dt, J = 10.5, 5.6 Hz, 4H), 1.75 (dd, J = 13.0, 7.2 Hz, 1 H), 2.10 (dd, J = 13.1, 8.7 Hz, 1H), 2.76 (d, J = 1 1.0 Hz, IH), 2.90 (d, J = 1 1.0 Hz, 1H), 3.15 (s, 3H), 3.53 (m, 4H), 3.83 (dd, J = 8.8, 7.2 Hz, lH), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.56 (s, 1H), 6.67 (q, J = 7.1 Hz, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.74 (m, 2H), 7.89 (m, 2H), 8.02 (m, 2H)
iu lH NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.51 (dt, J = 10.8, 5.6 Hz, 4H), 1.73 (dd, J = 13.1, 7.2 Hz, 1H), 2.08 (dd, J = 13.1, 8.8 Hz, 1H), 2.40 (s, 3H), 2.74 (d, J = 1 1.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, 1H), 3.15 (s, 3H), 3.53 (m, 4H), 3.81 (dd, J = 8.8, 7.2 Hz, IH), 4.18 (qd, J = 7.2, 1.7 Hz, 2H), 5.74 (s, 1H), 6.43 (d, J = 2.4 Hz, IH), 6.85 (q, J = 6.6 Hz, IH), 7.76 (dd, J = 1.7, 0.6 Hz, IH), 7.83 (m, 2H), 7.95 (m, 2H), 8.03 (m, 3H)
iv 'H NMR (400 MHz, MeOH-d4): δ ppm 1.05 (t, J = 7.4 Hz, 3H), 1.26 (m, 3H), 1.49 (dt, J = 10.7, 5.7 Hz, 4H), 1.78 (m, 3H), 2.08 (dd, J = 13.1, 8.8 Hz, IH), 2.25 (d, J = 14.0 Hz, IH), 2.39 (s, 3H), 2.75 (d, J = 11.0 Hz, IH), 2.88 (d, J = 11.0 Hz, IH), 3.53 (m, 4H), 3.83 (t, J = 8.0 Hz, IH), 3.95 (t, J = 6.4 Hz, 2H), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.76 (s, 1H), 6.41 (d, J = 2.3 Hz, IH), 6.75 (t, J = 6.7 Hz, IH), 6.98 (m, 2H), 7.58 (m, 3H), 7.71 (m, 2H), 7.96 (d, J = 2.4 Hz, IH)
ix 'H NMR (400 MHz, MeOH-d4): δ ppm 1.14 (t, J = 7.0 Hz, 3H), 1.26 (t, J = 7.1 Hz, 7H), 1.51 (dt, J = 10.8, 5.7 Hz, 4H), 1.73 (dd, J = 13.0, 7.2 Hz, IH), 2.08 (dd, J = 13.0, 8.8 Hz, IH), 2.39 (d, J = 1.7 Hz, 3H), 2.74 (d, J = 10.9 Hz, IH), 2.88 (d, J = 1 1.0 Hz, 1 IH), 3.31 (d, J = 16.3 Hz, 3H), 3.56 (s, 6H), 3.81 (dd, J = 8.7, 7.1 Hz, IH), 4.18 (m, 2H), 5.75 (s, IH), 6.42 (d, J = 2.4 Hz, IH), 6.82 (q, J = 6.5 Hz, IH), 7.47 (dd, J = 8.3, 2.0 Hz, 2H), 7.70 (d, J = 1.8 Hz, IH), 7.79 (m, 4H), 8.01 (d, J = 2.4 Hz, IH)
iy Ή NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 5H), 1.53 (dt, J = 9.7, 5.4 Hz, 8H), 1.74 (dd, J = 13.0, 7.3 Hz, 2H), 2.09 (dd, J = 13.1, 8.8 Hz, 2H), 2.76 (d, J = 11.0 Hz, 2H), 2.91 (d, J = 19.4 Hz, 7H), 3.36 (s, IH), 3.53 (m, 8H), 3.83 (dd, J = 8.7, 7.2 Hz, 2H), 4.18 (qd, J = 7.1 , 1.6 Hz, 4H), 4.97 (s, IH), 5.55 (s, 2H), 6.65 (q, J = 7.1 Hz, 2H), 7.62 (d, J = 8.1 Hz, 4H), 7.71 (m, 7H), 7.89 (m, 4H)
iz 'H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 4H), 1.51 (dt, J = 10.6, 5.5 Hz, 4H), 1.76 (dd, J = 13.1 , 7.3 Hz, IH), 2.1 1 (dd, J = 13.1, 8.8 Hz, IH), 2.40 (s, 3H), 2.78 (d, J = 1 1.1 Hz, IH), 2.91 (d, J = 1 1.0 Hz, IH), 3.54 (qq, J = 14.0, 7.5, 6.5 Hz, 4H), 3.88 (dd, J = 8.7, 7.4 Hz, IH), 4.19 (qd, J = 7.1, 1.7 Hz, 2H), 5.75 (s, IH), 6.43 (d, J = 2.4 Hz, IH), 6.83 (q, J = 6.6 Hz, IH), 7.73 (d, J = 1.6 Hz, IH), 7.84 (m, 4H), 7.99 (m, 3H)
j !H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (m, 7H), 1.53 (dt, J = 9.9, 5.5 Hz, 8H)}
I .77 (dd, J = 13.1, 7.4 Hz, 2H), 2.17 (m, 2H), 2,81 (d, J = 1 1.1 Hz, 2H), 2.93 (d, J =
I I .1 Hz, 2H), 3.33 (d, J = 12.6 Hz, IH), 3.52 (ddt, J = 17.5, 1 1.5, 5.2 Hz, 8H), 3.90 (dd, J = 8.6, 7.5 Hz, 2H), 4.20 (qd, J = 7.2, 1.7 Hz, 3H), 5.56 (s, 2H), 6.66 (q, J = 7.1 Hz, 2H), 7.64 (d, J = 8.1 Hz, 4H), 7.71 (d, J = 8.3 Hz, 4H), 7.79 (m, 4H), 7.96 (m, 4H)jb Ή NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz, 5H)} 1.53 (dt, J = 9.6, 5.3 Hz, 5H), 1.76 (dd, J = 13.1, 7.3 Hz, IH), 2.11 (dd, J = 13.1, 8.7 Hz, IH), 2.61 (m, 7H), 2.77 (d, J = 11.0 Hz, IH), 2.91 (d, J = 1 1.0 Hz, lH), 3.56 (m, 8H), 3.71 (t, J = 4.7 Hz, 5H), 3.85 (dd, J = 8.7, 7.2 Hz, IH), 4.19 (qd, J = 7.1, 1.6 Hz, 2H), 5.55 (s, IH), 6.66 (q, J = 7.2 Hz, IH), 7.63 (d, J = 8.1 Hz, 2H), 7,73 (m, 4H), 7.91 (m, 2H)
jc ]H NMR (400 MHz, MeOH-d4): 5 ppm 1.21 (dt, J = 33.8, 7.2 Hz, 4H), 1.51 (dt, J = 10.8, 5.4 Hz, 4H), 1.74 (dd, J = 13.1, 7.3 Hz, IH), 2.08 (m, IH), 2.40 (s, 3H), 2.58 (dt, J = 23.6, 5.8 Hz, 6H), 2.75 (d, J = 11.0 Hz, H), 2.88 (dd, J = 11.0, 5.9 Hz, IH), 3.32 (s, IH), 3.57 (m, 6H), 3,70 (t, J = 4.7 Hz, 4H), 3.82 (m, IH), 4.18 (qd, J = 7.1 , 1.7 Hz, 2H), 5.75 (s, IH), 6.43 (d, J = 2.4 Hz, IH), 6.82 (q, J = 6.6 Hz, IH), 7.72 (d, J = 1.5 Hz, IH), 7.81 (m, 4H), 7.96 (m, 4H)
jd Ή NMR (400 MHz, MeOH-d4): δ ppm 1.26 (td, J = 7, 1 , 1.3 Hz, 3H), 1.52 (dt, J =
9.5, 5.5 Hz, 4H), 1,74 (dd, J = 13.1, 7.2 Hz, IH), 2.09 (dd, J = 13.1, 8.8 Hz, IH), 2.75 (d, J = 1 1.1 Hz, IH), 2.89 (d, J = 10.9 Hz, 1H), 3.04 (d, J = 1.3 Hz, 3H), 3.1 (s, 3H), 3,52 (m, 4H), 3.82 (m, IH), 4.18 (qt, J = 7.1, 1.4 Hz, 2H), 5.55 (d, J = 1.3 Hz, IH), 6.66 (q, J = 7.1 Hz, IH), 7.51 (m, 2H), 7.68 (m, 6H)
je ]H MR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz, 4H), 1.53 (dt, J = 9.5, 5.3 Hz, 4H), 1.75 (dd, J = 13.0, 7.3 Hz, IH), 2.11 (dd, J = 13.1, 8.8 Hz, IH), 2.78 (t, J = 9.8 Hz, 3H), 2.91 (d, J = 1 1.0 Hz, 4H), 3.50 (m, 7H), 3.75 (s, 2H), 3.85 (dd, J = 8.8, 7.3 Hz, IH), 4.19 (qd, J = 7.2, 1.6 Hz, 2H), 5.55 (s, IH), 6.66 (q, J = 7.0 Hz, IH), 7.51 (m, 2H), 7.62 (d, J = 8.2 Hz, 2H), 7.72 (m, 4H)
jf lH NMR (400 MHz, MeOH-d4): δ ppm 1.26 (td, J = 7.4, 1.9 Hz, 8H), 1.50 (dt, J =
10.8, 5.8 Hz, 5H), 1.75 (dd, J = 13.1 , 7.4 Hz, IH), 2.10 (dd, J = 13.2, 8.9 Hz, IH), 2.39 (s, 3H), 2.86 (m, 8H), 3.26 (s, IH), 3.52 (m, 8H), 3.76 (s, 2H), 3.88 (dd, J = 8.8, 7.3 Hz, IH), 4.18 (ddtd, J = 7.7, 5.3, 3.6, 2.0 Hz, 2H), 4.93 (s, 2H), 5.74 (s, IH), 6.43 (d, J = 2.4 Hz, IH), 6.82 (q, J = 6.6 Hz, IH), 7.51 (dd, J = 8.3, 2.0 Hz, 2H), 7.75 (m, 7H), 8.01 (d, J = 2,4 Hz, IH)
jg !H NMR (400 MHz, MeOH-d4): δ ppm 1.31 (t, J = 7.2 Hz, 8H), 1.57 (s, 1 OH), 1.95 (dd, J = 13.4, 8.4 Hz, 2H), 2.37 (t, J = 1 1.1 Hz, 2H), 3.12 (m, 4H), 3.61 (m, 15H), 4.31 (m, 6H), 5.49 (s, IH), 5.62 (s, IH), 6.25 (d, J = 6.9 Hz, 2H), 6.50 (t, J = 6.8 Hz, 2H), 7.31 (d, J = 2.2 Hz, 2H), 7.46 (dd, J - 1 .4, 7.7 Hz, 4H), 7.65 (d, J = 8.5 Hz, 2H)} 7.79 (d, J = 7.1 Hz, 2H)
jh Ή NMR (400 MHz, MeOH-d4): 5 ppm 1.26 (t, J = 7.1 Hz, 3H), 1.50 (dt, J = 10.4, 5.5 Hz, 41-1), 1.74 (dd, J = 13.1, 7.2 Hz, IH), 2,08 (dd, J = 13.1, 8.8 Hz, IH), 2.39 (s, 3H), 2.75 (d, J = 1 1.0 Hz, IH), 2.89 (d, J = 1 1.0 Hz, IH), 3.53 (m, 4H), 3.83 (m, IH), 3.90 (s, 3H), 4.18 (qd, J = 7.2, 1.6 Hz, 2H), 5.75 (s, IH), 6.41 (d, J = 2.4 Hz, IH), 6,78 (q, J = 6.7 Hz, IH), 7.17 (t, J = 8.9 Hz, IH), 7.48 (m, 2H), 7.61 (d, J = 1.8 Hz, IH), 7.73 (m, 2H), 7.99 (d, J = 2.4 Hz, H)
ji 1H NMR (400 MHz, MeOH-d4): 6 pm 1.30 (d, J = 1 1.1 Hz, IH), 1.51 (q, J = 6.8, 6.0 Hz, 4H), 1.78 (dd, J = 13.0, 7.0 Hz, IH), 1.89 (s, 2H), 2.07 (dd, J = 13,1 , 9,1 Hz, IH), 2.40 (s, 3H), 2.68 (d, J = 1 1.1 Hz, IH), 2.95 (d, J = 11.1 Hz, IH), 3.03 (s, 3H), 3.11 (s, 3H), 3.22 (s, 2H), 3.45 (m, 3H), 3.63 (q, J = 7.9, 7.5 Hz, 3H), 5.75 (s, IH), 6.43 (d, J = 2.4 Hz, IH), 6.82 (q, J = 6.6 Hz, IH), 7.53 (d, J = 7.9 Hz, 2H), 7.70 (m, IH), 7.80 (m, 4H), 8.01 (d, J = 2.5 Hz, IH)
jj ¾ NMR (400 MHz, MeOH~d4): δ ppm 1.06 (t, J = 7.4 Hz, 4H), 1.30 (t, J = 7.1 Hz, 3H), 1.57 (m, 4H), 1.86 (m, 3H), 2,30 (m, IH), 3.09 (m, 3H), 3.54 (m, 4H), 4.03 (t, J = 6.4 Hz, 2H), 4.27 (m, 3H), 5.55 (s, IH), 6.64 (q, J = 7.2 Hz, IH), 7.12 (t, J = 8.8 Hz, IH), 7.37 (m, 2H), 7.58 (q, J = 8.4 Hz, 4H)
jk ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7,1 Hz, 5H), 1.50 (dt, J = 10.2, 5.2 Hz, 4H), 1.75 (dd, J = 13.1, 7.4 Hz, IH), 2.10 (dd, J = 13.1, 8.8 Hz, IH), 2.40 (s, 3H), 2.78 (d, J = 1 1.1 Hz, IH), 2.91 (d, J = 13.6 Hz, 4H), 3,52 (m, 4H), 3.88 (dd, J = 8.7,
7.3 Hz, IH), 4.18 (qd, J = 7.1, 1.6 Hz, 2H), 5.75 (s, IH), 6.43 (d, J = 2.4 Hz, IH), 6.82 (q, J = 6.5 Hz, IH), 7.70 (d, J = 1.7 Hz, IH), 7.78 (m, 4H), 7.90 (m, 2H), 8.01 (d, J =
2.4 Hz, IH)
jl Ή NMR (400 MHz, MeOH-d4): δ ppm 1 ,25 (m, 5H), 1,54 (dt, J = 11.2, 6.0 Hz, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, IH), 2.11 (dd, J = 13.1, 8,8 Hz, IH), 2.58 (s, 3H), 2.77 (d, J = 11.0 Hz, IH), 2,91 (d, J = 11.0 Hz, IH), 3.55 (h, J = 7.5 Hz, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, IH), 4.18 (qd, J = 7.1, 1.7 Hz, 2H), 5.58 (s, IH), 6.65 (q, J = 6.6 Hz, IH), 7.34 (d, J = 2.2 Hz, IH), 7.49 (dd, J = 8.5, 2.3 Hz, IH), 7.73 (m, 3H), 7.94 (ddd, J = 7.9, 1.8, 1.1 Hz, lH), 8.32 (s, IH)
jm Ή NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz, 4H), 1.54 (dt, J = 8.6, 4,8 Hz, 4H), 1.76 (dd, J = 13.1, 7,2 Hz, IH), 2.11 (dd, J = 13.1, 8.8 Hz, H), 2.73 (s, 7H), 2.91 (d, J = 10.9 Hz, IH), 3.55 (dp, J = 20.2, 7.2, 6.0 Hz, 4H), 3.84 (dd, J = 8.7, 7.2 Hz, lH), 4, 19 (qd, J = 7.1 , 1 .6 Hz, 2H), 5.59 (s, IH), 6.69 (q, J = 6.4 Hz, IH), 7.36 (d, J = 2,2 Hz, IH), 7.50 (dd, J = 8.5, 2.2 Hz, IH), 7.70 (dd, J = 13,1, 8.0 Hz, 2H), 7,85 (m, 2H), 8.34 (s, IH)
jn 'H NMR (400 MHz, MeOH-d4): δ ppm 1.30 (m, 10H), 1.52 (dt, J = 10.2, 5.7 Hz, 4H), 1.74 (dd, J = 13.1, 7.3 Hz, IH), 2,08 (m, IH), 2.83 (m, 4H), 3.20 (ddd, J = 1 1.9, 6.2, 3.0 Hz, 2H), 3.31 (s, IH), 3.49 (ddd, J = 30.2, 13.4, 6.0 Hz, 4H), 3,90 (dddd, J = 32.2, 15.9, 7.4, 5.0 Hz, 5H), 4.18 (qd, J = 7.2, 1.5 Hz, 2H), 4.64 (p, J = 6.0 Hz, IH), 5.52 (s, IH), 6.96 (m, 2H), 7.40 (m, 2H), 7.54 (m, 4H)
jo [H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (m, 4H), 1 ,54 (dt, J = 7.6, 4.8 Hz, 5H), 1.76 (dd, J = 13.1 , 7.3 Hz, IH), 2.11 (dd, J = 13.1, 8.8 Hz, IH), 2.77 (d, J = 1 1.0 Hz, I H), 2.92 (d, J = 18.5 Hz, 4H), 3.53 (m, 4H), 3.85 (dd, J = 8.7, 7.3 Hz, IH), 4.19 (qd, J = 7.1, 1.6 Hz, 2H), 4.93 (s, 7H), 5.52 (d, J = 19.1 Hz, IH), 6.63 (q, J = 6.7 Hz, IH), 7.29 (d, J = 2.2 Hz, IH), 7.46 (dd, J = 8.5, 2.3 Hz, III), 7.62 (m, 3H), 7.88 (dt, J = 7.7, 1.6 Hz, H), 8.37 (s, IH)
jp Ή NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.53 (dt, J = 7.7, 4.7 Hz, 4H), 1.75 (dd, J = 13.1, 7.2 Hz, IH), 2.10 (dd, J = 13, 1 , 8,8 Hz, IH), 2.76 (d, J = 11.0 Hz, IH), 2.90 (d, J = 1 1.0 Hz, IH), 3.06 (s, 3H), 3.12 (s, 3H), 3.51 (m, 4H), 3.83 (dd, J = 8.7, 7.2 Hz, H), 4.18 (qd, J = 7.1 , 1.6 Hz, 2H), 5.53 (s, IH), 6,70 (q, J = 6.7 Hz, IH), 7.32 (d, J = 2.2 Hz, IH), 7.56 (m, 5H), 7.79 (s, IH)
Ή NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 5H), 1.46 (m, 7H), 1.74 (dd, J = 13.1, 7.3 Hz, IH), 2.09 (dd, J = 13.1 , 8.7 Hz, IH), 2.75 (d, J = 11.0 Hz, IH), 2.89 (d, J = 11.0 Hz, IH), 3.52 (m, 4H)} 3.82 (dd, J = 8.7, 7.2 Hz, IH), 4.15 (m, 4H), 5.53 (s, IH), 6.62 (q, J = 7.1 Hz, IH), 7,12 (t, J = 8.7 Hz, IH), 7.38 (m, 2H), 7.58 (q, J = 8.4 Hz, 4H)
jr Ή NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1 ,39 (t, J = 7.0 Hz, 3H), 1.51 (m, 4H), 1.73 (dd, J = 13.1, 7.3 Hz, 1H), 2.08 (dd, J = 13.1, 8.8 Hz, IH), 2.74 (d, J = 11.0 Hz, IH), 2.88 (d, J = 11.0 Hz, IH), 3.49 (dtt, J = 19.6, 13.1, 6.9 Hz, 4H), 3.82 (dd, J = 8.8, 7.3 Hz, IH), 4.05 (q, J = 7.0 Hz, 2H), 4.18 (qd, J = 7.1 , 1.5 Hz, 2H), 5.53 (s, IH), 6.61 (q, J = 7.1 Hz, IH), 6.96 (m, 2H), 7.55 (m, 6H)
js [H NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.52 (m, 4H), 1.75 (dd, J = 13.1, 7.3 Hz, I H), 2.10 (dd, J = 13.1, 8.8 Hz, IH), 2.76 (d, J = 1 1.0 Hz, IH), 2.90 (d, J = 1 1.0 Hz, IH), 3.16 (s, 3H), 3.52 (m, 4H), 3.83 (dd, J = 8.7, 7.3 Hz, IH), 4.18 (qd, J = 7.2, 1.5 Hz, 2H), 5.53 (s, IH), 6.75 (q, J = 6.7 Hz, IH), 7.56 (m, 5H), 7.84 (d, J = 1.9 Hz, IH), 7.99 (m, 2H)
jt Ή NMR (400 MHz, MeOH-d4): δ ppm 1.13 (t, J = 7.2 Hz, 3H), 1.27 (q, J = 6.8 Hz, 7H), 1.55 (m, 4H), 1.81 (dd, J = 13.2, 7.6 Hz, IH), 2.18 (dd, J = 13.2, 8.7 Hz, IH), 2.86 (d, J = 1 1.2 Hz, IH), 2.98 (d, J = 1 1.2 Hz, IH), 3.36 (q, J = 7.1 Hz, 2H), 3.56 (m, 6H), 3.98 (t, J = 8.1 Hz, IH), 4.21 (qd, J = 7.2, 1.8 Hz, 2H), 5.54 (s, IH), 6.74 (q, J = 6.8 Hz, IH), 7.32 (d, J = 2.2 Hz, IH), 7.49 (m, 3H), 7.65 (m, 3H)
ju !H NMR (400 MHz, MeOH-d4): δ ppm 1.04 (dd, J = 6.8, 1.9 Hz, 6H), 1.26 (t, J = 7.2 Hz, 3H), 1.50 (dt, J = 10.7, 5.7 Hz, 4H), 1.73 (dd, J = 13.1, 7.2 Hz, IH), 2.07 (ddd, J = 13.0, 7.7, 4.9 Hz, 2H), 2.39 (s, 2H), 2.74 (d, J = 10.9 Hz, IH), 2.88 (d, J = 1 1.0 Hz, IH), 3.49 (d, J = 7.5 Hz, IH), 3.56 (d, J = 7.9 Hz, 3H), 3.78 (m, 3H), 4.17 (qd, J = 7.1 , 1.6 Hz, 2H), 5.75 (s, IH), 6.41 (d, J = 2.4 Hz, IH), 6.75 (q, J = 6.6 Hz, IH), 6.99 (m, 2H), 7.60 (dd, J - 8.7, 1.9 Hz, 3H), 7.72 (m, 2H), 7.97 (d, J - 2.4 Hz, IH)
jv ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.04 (s, 9H), .25 (t, J = 7.1 Hz, 3H), 1.48 (dt, J = 10.6, 5.7 Hz, 4H), 1.71 (dd, J = 13.1, 7.2 Hz, 1H), 2.05 (dd, J = 13.1, 8.8 Hz, IH), 2.39 (s, 3H), 2.72 (d, J = 1 1.0 Hz, IH), 2.86 (d, J = 11.0 Hz, IH), 3.52 (m, 4H), 3.64 (s, 2H), 3.80 (dd, J = 8.7, 7.1 Hz, IH), 4.17 (qd, J = 7.1, 1.5 Hz, 2H), 5.75 (s, IH), 6.41 (d, J = 2.3 Hz, IH), 6.76 (q, J = 6.6 Hz, IH), 6.98 (m, 2H), 7.57 (m, 3H), 7.70 (m, 2H), 7.96 (d, J = 2.4 Hz, IH)
jw Ή NMR (400 MHz, MeOH-d4): δ ppm
IH NMR (MeOH-d4) δ: 1.29 (t, J = 7.1 Hz, 7H), 1.53 (s, 8H), 1.79 (s, 2H), 2,14 (s, 2H), 2.81 (s, 2H), 2.94 (d, J = 10.8 Hz, 2H), 3.50 (s, 7H), 3.57 (s, 2H), 3.90 (t, J = 8.0 Hz, 2H), 4.22 (qd, J = 7.1, 1.7 Hz, 3H), 5.43 (s, IH), 6,51 (s, IH), 6.85 (s, IH), 7.25 (s, 1H), 7.48 (d, J = 9.7 Hz, 4H), 7.55 (d, J = 7.5 Hz, 2H), 7.79 (s, 4H), 8.13 (s, 2H)jx Ή NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J - 7.1 Hz, 3H), 1.49 (dt, J = 10.8, 5.8 Hz, 4H), 1.73 (dd, J = 13.1 , 7.2 Hz, 1H), 2.03 (m, 3H), 2.39 (s, 3H), 2.73 (d, J = 1 1.0 Hz, 1H), 2.85 (m, 3H), 3.53 (m, 4H), 3.81 (dd, J = 8.7, 7.1 Hz, 1H), 4,17 (m, 4H), 5.75 (s, 1H), 6.40 (d, J = 2.3 Hz, 1H), 6.77 (dd, J = 17.0, 7.9 Hz, 2H), 7.36 (dq, J = 4.4, 2.5 Hz, 2H), 7.56 (d, J = 1.8 Hz, 1H), 7.69 (m, 2H), 7.96 (d, J = 2.3 Hz, 1H)jy ]H NMR (400 MHz, MeOH-d4): δ 1.27 (dd, J = 7.9, 6.4 Hz, 4H), 1.54 (dt, J = 10.7, 5.6 Hz, 4H), 1.76 (dd, J = 13.2, 7.4 Hz, 1H), 2.12 (dd, J = 13.1, 8.8 Hz, 1H), 2.78 (m, 3H), 2.92 (m, 3H), 3.53 (m, 6H), 3.76 (s, 2H), 3.85 (dd, J = 8.7, 7.2 Hz, 1H), 4.19 (qd, J = 7.1, 1.7 Hz, 2H), 5.51 (d, J = 15.6 Hz, 1 H), 6.72 (q, J = 6.6 Hz, 1H), 7.33 (d, J = 2.2 Hz, 1H), 7.51 (m, 3H), 7.66 (m, 2H), 7.79 (s, 1H)
jz !H NMR (400 MHz, MeOH-d4): δ 0.46 (m, 4H), 1.27 (m, 4H), 1.53 (dt, J = 1 .2, 5.6 Hz, 4H), 1.72 (m, 2H), 2.13 (dd, J = 13, 1 , 8.8 Hz, 1H), 2.58 (s, 2H), 2.73 (s, 2H), 2.80 (d, J - 1 1.1 Hz, 1H), 2.93 (d, J = Π .0 Hz, 1H), 3.52 (ddd, J = 25.7, 12.3, 6.8 Hz, 6H), 3.76 (s, 2H), 3.89 (dd, J = 8.7, 7.3 Hz, 1H), 4.19 (qd, J = 7.1, 1.7 Hz, 2H), 5.52 (d, J = 17,0 Hz, 1H), 6.71 (q, J = 6.7 Hz, 1H), 7.33 (d, J = 2.3 Hz, 1H), 7.57 (m, 5H), 7.80 (s, 1H)
ka Ή NMR (400 MHz, MeOH-d4): δ ppm 1.25 (t, J = 7.1 Hz, 3H), 1.50 (dt, J = 10.3, 5.3 Hz, 4H), 1.73 (dd, J = 13.1, 7.3 Hz, 1H), 2.07 (dd, J = 13.1, 8.8 Hz, 1H), 2.41 (s, 3H), 2.75 (d, J = 11.0 Hz, 1H), 2.88 (d, J = 11.0 Hz, III), 3.51 (m, 4H), 3.82 (dd, J = 8.8, 7.2 Hz, 1H), 4.17 (qd, J = 7.1, 1.6 Hz, 2H), 5.76 (s, 1H), 6.45 (d, J = 2.4 Hz, 1H), 6.88 (q, J = 6.6 Hz, 1H), 7.92 (m, 3H), 8.07 (d, J = 2.4 Hz, 1H), 8.29 (m, 3H), 8.52 (d, J = 8.9 Hz, 1H), 9.32 (d, J = 5.9 Hz, 1H)
kb 'H NMR (400 MHz, MeOH-d4): 8 ppm 1.35 (t, J=7.22 Hz, 3 H) 1.65 - 1.91 (m, 4 H) 2.12 (dd, J=13.67, 8.79 Hz, 1 H) 2.53 (dd, J=13.67, 8.79 Hz, 1 H) 3.35 (s, 2 H) 3.56 - 3.91 (m, 4 H) 4.35 (qd, J=7.06, 3.03 Hz, 2 H) 4.65 (t, J=8.69 Hz, 1 H) 6.66 (d, J=5.66 Hz, 1 H) 7.02 (d, J=2.34 Hz, 1H) 7.69 - 7.78 (m, 2 H) 7.79 - 7.88 (m, 1 H) 8.29 (d, J=1.37 Hz, 1 H)
kc ¾ NMR (400 MHz, MeOH-d4): δ ppm 1.35 (t, J=7.13 Hz, 3 H) 1.40 (s, 9 H) 1.64 - 1.85 (m, 4 H) 2.03 - 2.18 (m, 1 H) 2.43 - 2.61 (m, 1 H)
3.53 - 3.87 (m, 4 H) 4.27 - 4.43 (m, 2 H) 4.56 - 4.70 (m, 1 H) 5.51 (s, 1 H) 6.56 (d, J=2.34 Hz, 1 H) 7.30 - 7.42 (m, 1 H) 7.53 - 7.61 (m, 1 H) 7.69
(d, J-1.95 Hz, 2 H) 8.01 (d, J=2.54 Hz, 1 H)
kd Ή NMR (400 MHz, MeOH-d4): δ ppm 1.22 - 1 ,42 (m, 9 H) 1 ,51 - 1.72 (m, 4 H) 1.90 - 2.09 (m, 1 H) 2.33 - 2.52 (m, 1 H) 3.09 (s, 1 H) 3.21 (d, J=4.69 Hz, 2 H) 3.40 - 3.72 (m, 4 H) 4.31 (dd, J=7.13, 2.25 Hz, 2 H) 4.48 (s, 1 H) 5.64 (s, 1 H) 6.47 (d, J=2.34 Hz, 1 H) 7.02 (d, J=6.64 Hz, 1 H) 7.43 - 7.60 (m, 2 H) 7.72 (d, J-8.59 Hz, 1 H) 7.95 (d, J=2.34 Hz, 1 II)
ke Ή NMR (400 MHz, MeOH-d4): δ ppm 0.68 - 0.95 (m, 2 H) 1.05 (dd, J=8.40, 2.15 Hz, 2 H) 1.35 (t, J=7.13 Hz, 4 H) 1.63 - 1.89 (m, 4 H) 1.98 - 2.18 (m, 2 H) 2.44 - 2.63 (m, 1 H) 3.78 (d, J=5,08 Hz, 4 H) 4.35 (d, J=7.03 Hz, 2 H) 4.63 (s, 1 H) 6.31 (d, J=2.34 Hz, 1 H) 7.09 (d, J=6.25 Hz, 1 H) 7.51 - 7.67 (m, 2 H) 7.73 (d, J=8.20 Hz, 1 H) 7.93 (d, J=2.54 Hz, 1 H)
kf Ή NMR (400 MHz, MeOH-d4): δ ppm 1.35 (t, J=7.13 Hz, 4 H) 1.74 (br. s„ 4 H) 2.04 - 2.15 (m, 1 H) 2.34 (s, 3 H) 2.37 (s, 3 H) 2.44 - 2.58 (m, 1 H) 3.31 (d, J=2.34 Hz, 2 H) 3.54 - 3.89 (m, 3 II) 4.34 (dd, J=7.13, 3.22 Hz, 2 H) 4.61 (s, 1 H) 6.10 (s, 1 H) 6.51 - 6.65 (m, 1 H) 7.03 (d, J=2.15 Hz, 1 H) 7.28 (s, 1 H) 7.42 - 7.50 (m, 1 II) 7.54 (s, 1 H) 7.76 - 7.88 (m, 2 H) 7.90 - 8.01 (m, 1 H) 8.33 (s, 1 H)
kg 'H NMR (400 MHz, MeOH-d4): δ ppm 1.29 (t, J = 7.1 Hz, 3H), 1.55 (s, 3H), 1.58 (d, J = 5.8 Hz, IH), 1.88 (m, IH), 2.29 (m, 6H), 3.04 (m, 2H), 3.43 (s, 2H), 3.56 (s, 2H), 4.24 (m, 2H), 6.68 (q, J = 6.9 Hz, 1H)} 7.17 (d, J = 7.9 Hz, IH), 7.36 (m, 2H)} 7.45 (m, IH), 7.52 (s, 2H), 7.53 (d, J = 2.8 Hz, IH), 7.63 (dd, J = 8.2, 2.0 Hz, IH), 7.73 (d, J = 8.2 Hz, IH)
kli 'H MR (400 MHz, MeOH-d4): 6 pm 1.05 (t, J = 7.4 Hz, 3H), 1.26 (td, J = 7,1, 2.1 Hz, 3H), 1,50 (s, 3H), 1.53 (d, J = 5.7 Hz, IH), 1 ,79 (m, 3H), 2.09 (dd, J = 13.1, 8,8 Hz, IH), 2.75 (d, J = 11.0 Hz, IH), 2.89 (d, J = 1 1.0 Hz, IH), 3.50 (s, 3H), 3.83 (dd, J = 8,8, 7.2 Hz, IH), 4.02 (t, J = 6.5 Hz, 2H), 4.17 (m, 2H), 5.46 (s, IH), 6.67 (q, J = 6.7 Hz, IH), 7,12 (t, J = 8.6 Hz, IH), 7.40 (m, 4H), 7.52 (s, 4H), 7,54 (s, IH), 7.62 (dd, J = 8.2, 2, 1 Hz, IH), 7.74 (d, J = 8.3 Hz, IH)
ki ¾H NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz, 3H), 1 ,53 (dd, J = 11.2, 5.2 Hz, 5H), 1.75 (dd, J = 13.1, 7.3 Hz, IH), 2.10 (dd, J = 13.1, 8.8 Hz, IH), 2.76 (d, J = 1 1.0 Hz, IH), 2.90 (d, J = 1 1.0 Hz, IH), 3.49 (m, 2H), 3.51 (s, 3H), 3.84 (dd, J = 8.7, 7.3 Hz, lH), 4.18 (qd, J - 7.1 , 1.6 Hz, 2H), 5.44 (s, IH), 6.66 (q, J = 6.9 Hz, IH), 7.26 (m, IH), 7.45 (m, 8H), 7.70 (d, J = 7.2 Hz, IH)
kj Ή NMR (400 MHz, MeOH-d4): δ ppm 1.27 (t, J = 7.1 Hz, 3H), 1.53 (dd, J = 11.0, 5.2 Hz, 4H), 1.77 (dd, J = 13.2, 7.4 Hz, IH), 2.13 (dd, J = 13.1 , 8.8 Hz, IH), 2.80 (d, J = 11.1 Hz, IH), 2.93 (d, J = 1 1.1 Hz, IH), 3.46 (m, IH), 3.53 (m, 2H), 3.91 (t, J = 8,1 Hz, IH), 4.19 (qd, J = 7.1, 1.4 Hz, 2H), 5.47 (s, IH), 6.69 (q, J = 6.9 Hz, IH), 7.35 (m, IH), 7.45 (m, 4H), 7.54 (d, J = 4.6 Hz, 4H), 7.65 (m, 3H), 7.77 (d, J = 8.2 Hz, IH)kk Ή NMR (400 MHz, MeOH-d4): δ ppm 1.25 (t, J = 7.1 Hz, 3H), 1.51 (m, 4H), 1.74 (dd, J = 13.1, 7.4 Hz, IH), 2.10 (dd, J = 13.1 , 8.8 Hz, IH), 2.29 (d, J = 9.9 Hz, 6H), 2.39 (s, 3H), 2.77 (d, J = 11.1 Hz, IH), 2.90 (d, J = 11.1 Hz, IH), 3.54 (tq, J = 14.0, 7.9, 6.7 Hz, 4H), 3.88 (dd, J = 8.7, 7.4 Hz, IH), 4.17 (m, 2H), 5.74 (s, IH), 6.41 (d, J =
2.3 Hz, IH), 6.77 (q, J = 6.6 Hz, IH), 7.19 (d, J = 7.8 Hz, IH), 7.36 (dd, J = 7.6, 2.1 Hz, IH), 7,42 (d, J = 1.5 Hz, IH), 7.59 (d, J - 1.9 Hz, IH), 7.72 (m, 2H), 7,97 (d, J =
2.4 Hz, IH)
kl Ή NMR (400 MHz, MeOH-d4): δ ppm 1.26 (t, J = 7.1 Hz, 3H), 1.51 (dd, J = 11.1, 5.8 Hz, 5H), 1.74 (dd, J = 13.1, 7.3 Hz, IH), 2.09 (dd, J = 13.1 , 8.8 Hz, IH), 2.39 (s, 3H), 2.76 (d, J = 11.0 Hz, 1 H), 2.89 (d, J = 11.0 Hz, IH), 3.55 (d, J = 5.0 Hz, 4H), 3.85 (dd, J = 8.7, 7.2 Hz, IH), 4.18 (m, 2H), 4.65 (s, 2H), 5.78 (s, IH), 6.41 (d, J = 2.4 Hz, IH), 6.87 (q, J = 6.5 Hz, IH), 7.47 (dd, J = 10.9, 8,2 Hz, 3H), 7.59 (m, 2H), 7.79 (dd, J = 8.3, 2.1 Hz, IH), 7.93 (d, J = 2.3 Hz, 2H)
km Ή NMR (400 MHz, MeOH~d4): δ ppm 7.61 - 7.49 (m, 4H), 7.35 - 7.27 (m, 2H), 6.77 (dd, J = 8.4, 1 ,8 Hz, IH), 6,60 (q, J = 7.3 Hz, 1 H), 5.55 - 5.46 (m, IH), 4.24 - 4.13 (m, 4H), 3.83 (dd, J = 8.8, 7.2 Hz, IH), 2.93 - 2.71 (m, 4H), 2.14 - 1 ,94 (m, 3H), 1 ,74 (dd, J = 13.1, 7.3 Hz, IH), 1.56 - 1.48 (m, IH), 1.51 (s, 3H), 1.27 (td, J = 7.1, 2.0 Hz, 3H).
kn !H NMR (400 MHz, MeOH-d4): δ ppm 8.71 (d, J - 5.2 Hz, 2H), 8,02 (td, J = 7,7, 1.7 Hz, IH), 7.78 - 7.68 (m, 3H), 7.51 (tt, J = 7.9, 3.3 Hz, 5H), 6,92 (d, J = 6.5 Hz, IH), 5.81 (d, J = 3,8 Hz, 2H), 4.18 (qd, J = 7.1, 1.7 Hz, 2H), 3.83 (s, IH), 3.56 (s, 6H), 3.57 - 3.46 (m, IH), 2.89 (d, J = 11.0 Hz, 2H), 2.76 (d, J = 1 1.0 Hz, 2H), 2.09 (dd, J = 13.1, 8.9 Hz, IH), 1.74 (dd, J = 13.1, 7.3 Hz, IH), 1.52 (dd, J = 10.9, 5.5 Hz, 5H), 1.31 - 1.22 (m, 6H)
63 ko 'H NMR (400 MHz, MeOH-d4): δ ppm 8.99 (d, J = 4.9 Hz, 2H), 8.03 (s, 1 H), 7.73 (dd, J = 15.2, 7.7 Hz, 2H), 7.60 - 7.48 (m, 2H), 5.69 (s, IH), 4.18 (q, J = 7,1 Hz, 2H), 3.83 (t, J = 8.1 Hz, IH), 3.54 - 3.43 (m, 4H), 2.89 (d, J = 1 1.1 Hz, IH), 2.75 (d, J = 1 1.0 Hz, IH), 2.14 - 2.04 (m, IH), 1.74 (dd, J = 13.0, 7.4 Hz, IH), 1.50 (dd, J = 10.6, 5.5 Hz, 5H), 1.26 (t, J = 7.2 Hz, 4H)
63kp Ή NMR (400 MHz, MeOH-d4): δ ppm 7.97 (s, IH), 7.76 (s, 2H), 7.66 (d, J = 16.1 Hz, 2H)5 7.49 (d, J = 7.9 Hz, IH), 7.25 (d, J = 8.1 Hz, IH), 6.77 (d, J = 7.1 Hz, I II), 6.41 (s, IH), 5.74 (d, J = 2.7 Hz, IH), 4.68 (s, 2H), 4.18 (d, J = 7.6 Hz, 2H), 3.84 (t, J = 8.1 Hz, IH), 3.56 (s, 3H), 3.49 (s, IH), 3.30 (d, J = 3.4 Hz, 9H), 2.89 (d, J = 11.1 Hz, IH), 2.76 (d, J = 1 1.0 Hz, IH), 2.37 (d, J = 14.1 Hz, 5H), 1.79 - 1.69 (m, IH), 1.51 (d, J = 8.8 Hz, 4H), 1.30 - 1.21 (m, 4H)
63kq ¾ NMR (400 MHz, MeOH-d4): δ ppm 7.98 (s, IH), 7.76 (d, J - 5.1 Hz, 2H), 7.63 (s, IH), 7.48 (d, J = 13.3 Hz, 3H), 6.77 (d, J = 6.8 Hz, IH), 6.41 (s, IH), 5.74 (s, IH), 4,66 (s, 2H), 4.18 (d, J = 7.4 Hz, 2H), 3.82 (t, J = 8.2 Hz, IH), 3.56 (s, 3H), 3,50 (s, lH), 2.89 (d, J = 11.0 Hz, 1H), 2.75 (d, J = 11.1 Hz, lH), 2.39 (s, 6H), 1.74 (dd, J = 13.0, 7.2 Hz, IH), 1.51 (s, 4H), 1.30 - 1.22 (m, 3H)
63kr !H NMR (400 MHz, MeOH-d4); δ ppm 8.43 (d, J = 2.5 Hz, IH), 7.98 (d, J = 10.3 Hz, 2H), 7.79 (d, J = 8.3 Hz, IH), 7.71 (d, J = 8.5 Hz, IH), 7.63 (s, IH), 6.83 (dd, J = 19.6, 7.7 Hz, 2H), 6.42 (d, J = 2.3 Hz, IH), 5.74 (s, IH), 4.35 (q, J = 7.0 Hz, 2H), 4.17 (q, J = 7.1 Hz, 2H), 3.55 (s, 3H), 3.48 (d, J = 13.0 Hz, IH), 2.88 (d, J = 11.0 Hz, IH), 2.74 (d, J = 11.0 Hz, IH), 2.39 (s, 3H), 2.07 (dd, J = 13.0, 8.9 Hz, IH), 1.73 (dd, J - 13.0, 7.2 Hz, IH), 1.50 (d, J = 8.3 Hz, 4H), 1.38 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H).
63ks Ή NMR (400 MHz, MeOH-d4): δ ppm 8,46 (s, IH), 7.99 (s, 2H), 7.83 - 7.69 (m, 2H), 7.64 (s, IH), 6.80 (d, J = 5.3 Hz, IH), 6.42 (s, IH), 5.74 (s, IH), 4.18 (d, J = 7.3 Hz, 2H), 3.94 (d, J = 2.7 Hz, 3H), 3.86 (t, J = 8.1 Hz, IH), 3.56 (s, 3H), 3.50 (s, IH), 2.91 (d, J = 1 1.0 Hz, IH), 2.77 (d, J = 11.6 Hz, IH), 2.39 (d, J = 2.7 Hz, 3H), 2.10 (t, J = 10.9 Hz, IH), 1.80 - 1.70 (m, IH), 1.51 (s, 4H), 1.26 (dd, J = 8.3, 5,7 Hz, 3H).
63kt ]H NMR (400 MHz, MeOH-d4): δ ppm 7.67 (d, J = 8.5 Hz, IH), 7.44 (ddd, J = 8.0, 4.8, 2.6 Hz, 2H), 7.32 - 7.24 (m, 2H), 7.07 (dd, J = 8.4, 2.5 Hz, IH), 6.99 (d, J = 7.6 Hz, IH), 6.76 (q, J = 6,9 Hz, IH), 5.51 (s, IH), 4.27 (dd, J = 7.0, 2.0 Hz, IH), 4.25 - 4.13 (m, 4H), 3.76 (s, 2H), 3.58 (s, 2H), 3.51 (d, J = 14.9 Hz, 2H), 3.42 (s, 3H), 3.08 (d, J = 1 1 ,4 Hz, IH), 2.99 (d, J = 1 1.4 Hz, IH), 2.28 (dd, J = 13.3, 8.7 Hz, IH), 1.88 (dd, J = 13.3, 8.0 Hz, IH), 1.57 (p, J = 5.4 Hz, 4H), 1.29 (t, J = 7.1 Hz, 3H)
63ku ¾ NMR (400 MHz, MeOH-d4): δ ppm 8.97 (d, J = 1.5 Hz, IH), 8.80 (dd, J = 2.6, 1.5 Hz, IH), 8.71 (d, J = 2.6 Hz, IH), 7.77 (d, J = 8.3 Hz, IH), 7.64 - 7.55 (m, IH), 6.87 (q, J = 6,7 Hz, IH), 5.62 (s, IH), 4.23 - 4.13 (m, 2H), 3.82 (dd, J = 8.7, 7.2 Hz, IH), 3.60 - 3.42 (m, 3H), 2.89 (d, J = 1 1.0 Hz, IH), 2.75 (d, J = 11.0 Hz, IH), 2,09 (dd, J = 13.1, 8.7 Hz, IH), 1.74 (dd, J = 13.1, 7.2 Hz, IH), 1.51 (dt, J = 10.9, 5.6 Hz, 3H), 1 ,26 (t, J = 7.1 Hz, 2H)
Example 64a: (S)-Octyl 8-(2-amino-6-((R)-l-(4-chloiO-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxyIate
Figure imgf000358_0001
To a flask equipped with a Dean Stark trap were added (25)-8-[2-amino-6-[(17f)-l -[4-chloro-2- (3-methyl pyrazol-l-yl)phenyl]-2>2,2-tnfluoiOethoxy]pyrimidin-4-yl]-3,8-diazaspiiO[4.5]decane- 2-caiboxylic acid (1 g, 1.78 mmol), toluene (25 mL), and ^-toluene sulfonic acid monohydrate (336 mg, 1.77 mmol), and -octanol (690 mg, 5.30 mmol). The reaction mixture was heated to reflux for 48 h, cooled to RT, and concentrated in vacuo. Purification on a 120 g Isco RediSep silica cartridge (CH2Ch/MeOH/ NH4OH) provided the title compound as a white solid.
Applying the generic scheme below, the following examples of Table 19a were prepared as described above for (S)-octyl 8-(2-amino-6-((R)-l-(4-chloiO-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoiOetl oxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate (Example 64a), using the appropriate alcohol.
Figure imgf000358_0002
Table 19a.
Figure imgf000359_0001
Figure imgf000359_0002
64h (S)-isopropyl 8-(2-amino-6-((R)-l -(4-chloi -2-(3-methyl- 622
lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoiOethoxy)pyrimidm-
4-yl)-2,8-diazaspii'o[4.5]decane-3-carboxylate
Table 19b.
NMR Data for Compounds of Table 19a
Ex. NMR
No.
64a lH NMR (400 MHz, MeOH-d4): δ ppm 0.82 - 0.96 (m, 3 H), 1.20 - 1.47 (m, 10 H), 1.53 - 1.79 (m, 6 H), 2.04 (dd, J = 13.6, 8.8 Hz, 1 H), 2.38 (s, 3 H), 2.49 (dd, J = 13.6, 8.8 Hz, 1 H), 3.28 (s, 2 H), 3.42 - 3.85 (m, 4 H), 4.16 - 4.39 (m, 2 H), 4.60 (t, J = 8.8 Hz, 1 H), 5.81 (s, 1 H), 6.42 (d, J = 2.2 Hz, 1 H), 6.85 (q, J = 6.6 Hz, 1 H), 7.46 - 7.60 (m, 2 H), 7.71 (d, J = 8.3 Hz, 1 H), 7.93 (d, J = 2.4 Hz, 1 H)
64b Ή NMR (400 MHz, MeOH-d4): δ ppm 1.50 - 2.10 (m, 13 H), 2.38 (s, 3 H), 2.45 (dd, J = 13.6, 8.8 Hz, 1 H), 3.27 (d, J = 1.2 Hz, 2 H), 3.43 - 3.76 (m, 4 H), 4.55 (t, J = 8.7 Hz, 1 H), 5.26 - 5.39 (m,l H), 5.74 (s, 1 H), 6.42 (d, J = 2.3 Hz, 1 H), 6.83 (q, J = 6,6 Hz, 1 H), 7.45 - 7.59 (m, 2 H), 7.71 (d, J = 8.4 Hz, 1 H), 7.93 (d, J = 2.3 Hz, 1 H)
64c 'H NMR (400MHz, MeOH-d4): δ ppm 0.94 (t, J=7.2Hz, 3H), 1.35-1.39 (m, 4H), 1.52- 1.56 (m, 4 H), 1.64-1.71 (m, 2H), 1.74 - 1.79 (m, IH), 2.08-2.14 (m, IH), 2.40 (s, 3 H), 2.77 (d, J=10.8 Hz ,1H), 2.92 (d, J=10.8 Hz, IH), 3.48-3.58 (m, 4 H), 3.83-3.87 (m, IH), 4,13-4, 18 (m, 2H), 5.69 (s, 1 H), 6.43 (d, J=2.0 Hz, IH), 6.81 -6.86 (m, IH), 7.51-7.55 (m, 2H), 7.72 (d, J=8.4 Hz, IH), 7.95 (d, J=2.0 Hz, IH)
64d ¾ NMR (400MHz, MeOH-d4): 5 ppm 1.31-1.56 (m, 10H), 1.75-1.80 (m, 3H), 1.85 - 1.89 (m, 2H), 2.08-2.13 (m, IH), 2.39 (s, 3H), 2.76 (d, J=10.8 Hz ,1 H), 2.93 (d, J=10.8 Hz, IH), 3.50-3.58 (m, 4H), 3.81-3.84 (m, IH), 4.77-4.83 (m, IH), 5.69 (s, 1 H), 6.42 (d, J=2.0 Hz, IH), 6.81-6.86 (m, IH), 7.51-7.55 (m, 2H), 7.72 (d, J=8.4 Hz, IH), 7.95 (d, J=2.4 Hz, IH)
64e Ή NMR (400MHz, MeOH-d4): δ ppm 0.98 (t, J=7.6Hz, 3H), 1.54-1.59 (m, 4 H), 1.66 (m, 2H), 1.81 - 1 ,86 (m, IH), 2.17-2.23 (m, IH), 2.40 (s, 3H), 2.89 (d, J=l 1.2 Hz ,1H), 3.00 (d, J=l 1.2 Hz, IH), 3.47-3.62 (m, 4H), 4.03 (t, J=8.0 Hz, IH), 4.11-4.18 (m, 2H), 5.70 (s, IH), 6.43 (d, J=2,4 Hz, IH), 6.84 (q, IH), 7,51-7.55 (m, 2H), 7.73 (d, J=8.4 Hz, IH), 7.95 (d, J=2,4 Hz, IH)
64f Ή NMR (400MHz, MeOH-d4): δ ppm 0.98 (s, 9H), 1.50-1.58 (m, 4 H), 1.77-1.82 (m, IH), 2.12-2.17 (m} IH), 2.40 (s, 3H), 2.79 (d, J=l 1.2 Hz ,1H), 2.94 (d, J=l 1.2 Hz, IH), 3.52-3.58 (m, 4H), 3.83-3.93 (m, 3H), 5.70 (s, 1 H), 6.43 (d, J=2.4 Hz, IH), 6,81-6.86 (m, IH), 7.52-7.55 (m, 2H), 7.73 (d, J=8.4 Hz, IH), 7.95 (d, J=2.4 Hz, IH)
64g 'H NMR (400MHz, MeOH-d4): δ ppm 0.95 (t, J=7.6Hz, 3H), 1.37-1.43 (m, 2H), 1.50- 1.54 (m, 4H), 1.60-1 ,67 (m, 2H), 1.72-1.77 (m, I H), 2.06-2.12 (m, IH), 2.38 (s, 3 H), 2.75 (d, J=1 1.2 Hz , 1 H), 2.90 (d, J=11.2 Hz, I H), 3,45-3.58 (m, 4 H), 3.83-3.86 (m, IH), 4.10-4.20 (m, 2H), 5.67 (s, IH), 6.40 (d, J=2.4 Hz, IH), 6.80-6.85 (m, 1 H), 7.50-7.53 (m, 2H), 7.71 (d, J=8.0 Hz, IH), 7.93 (d, J=2.0 Hz, IH)
64h lK NMR (400MHz, MeOH-d4): δ ppm 0.85 (d, J=6,8Hz, 6H), 1.42-1.47 (m, 4H), 1.68- 1.73 (m, IH), 1 .82-1.89 (m, IH), 2.05-2.10 (m, IH), 2.28 (s, 3H), 2.74 (d, J=I 1.2 Hz , 1
Figure imgf000361_0001
Example 65a: (S)-Tert-butyl 8-(2-amino-6-((R)-l-(4-chIoro-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxj ate
Figure imgf000361_0002
Step 1 : To a mixture of (S)-8-(2-amino-6-((R)-l -(4-chloiO-2-(3-methyl-lH-pyrazol-l-yl)phenyl)- 2}2,2-trifluoiOethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid (2.8 g, 4.1 mmol) in /-BuOH (50 mL) were added BOC20 (3.5 g, 16.5 mmol) and DMAP (0.201 g, 1.65 mmol), and the reaction was heated to 50°C for 45 min. Then the reaction was cooled to RT and concentrated in vacuo. Purification on a 220 g Isco RediSep silica cartridge (EtO Ac/heptane) provided (S)-2-benzyI 3-tert-butyl 8-(2-amino-6-((R)- 1 -(4- chloro-2-(3 -methyl- lH-pyrazol-l-yl)phenyl)-2}2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid .
Step 2: To a solution of (S)-2-benzyi 3-tert-butyl 8-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH- pyrazol-l-yl)phenyl)-2,2,2-trifiuoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-253- dicarboxylate (1.35 g, 1.7 mmol) in EtO Ac (130 mL) was added 5% (w/w) Pd/C (130 mg). The solution was degassed, charged with 1 atm ¾ (balloon), and stirred at RT for 3.5 h. Then the solids were filtered through celite, washed with EtOAc/methanol, and the filtrate was
concentrated in vacuo. Purification on a 220 g Isco RediSep silica cartridge (GH C /MeOHY NH4OH) provided the title compound as an off-white solid.
Applying the generic scheme below, the following examples of Table 20a were prepared as described above for (S)-tert-butyl 8-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoiOethoxy)pyrimidin-4-yl)-2t8-diazaspiiO[4.5]decane-3-caiboxylate (Example 65).
Figure imgf000362_0001
Table 20a.
Figure imgf000362_0002
Figure imgf000362_0003
Figure imgf000363_0001
Table 20b.
NMR Data for Compounds of Table 20a
Figure imgf000363_0002
Example 66a: (S)-2-(Dimethylamino)ethyl 8-(2-amino-6-((R)-l-(4-chIoro-2-(3-niethyl-lH- pyrazol-l-yI)phenyl)-2,2,2-triflxioroethoxy)pyrimidin-4-yl)-2,8- !iazaspiro[4,5]ilecane-3- carboxylate
Figure imgf000364_0001
Step J: To a mixture of (S)-8-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)- 2!2,2-trifliioiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (85 mg, 0.16 mmol) in THF (10 mL) was added BOC20 (4 g, 18.6 mmol) in THF (10 mL), and the reaction mixture was stirred at RT for 16 h. Then the reaction was diluted with CH2C12, cooled to 0 °C, and the pH adjusted to 2 with 2 N HC1. The reaction mixture was then extracted CH2Cl2 and concentrated in vacuo to provide (S)-8-(2-amino-6-((R)-l -(4-chloro-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoroefhoxy) pyrimidin-4-yi)-2-(tert~butoxycarbonyl)~2,8- diazaspiro[4.5]decane-3-carboxylic acid as an off-white solid that was used directly without further purification . Step 2: To a solution of (S)-8-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoiOethoxy)pyrimidin-4-yl)-2-(tert-butoxycarbonyl)-2J8-diazaspii
[4.5]decane-3-carboxylic acid (1 ,6 g, 2.45 mmol) in DMF (24 mL) were added (2-chloro-ethyl)- dimethyl-amine hydrochloride (535 mg, 3.7 mmol) and K2CO3 (1.0 g, 7.4 mmol), and the reaction mixture was heated at 65 °C for 16 h. Then the reaction was cooled to RT, partitioned between EtOAc and water, and extracted. The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. Purification via prep-HPLC column chromatography (CH2Cl2/MeOH/NH40H) provided (S)-2-tert-butyl 3-(2-(dimethylamino)ethyI) 8-(2-amino-6-((R)-l -(4-chloiO-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifiuoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid. Step 3: To a solution of (S)-2-tert-butyl 3-(2-(dimethylamino)ethyl) 8-(2-amino-6-((R)-l-(4- chloiO-2-(3-methyl-lH-pyrazol-l-yl)plienyl)-2,2,2-ti'ifluoiOethoxy)pyrimidin-4-yl)-2,8- diazaspii [4,5]decane-2,3-dicarboxylate (1.4 g, 1.86 mmol) in CH2CI2 (9 mL) was added TFA (4.5 mL), and the reaction was stirred at RT for 2 h. Then the reaction was concentrated in vacuo and the residue was partitioned between CH2C12 and aqueous NallCC , and extracted. The combined organic layers were washed with brine, dried over Na2S04; and concentrated in vacuo. Purification via prep-HPLC column chromatography (CH2Cl2/EtOH/NH4OH ) provided the title compound as an off-white solid,
Applying the generic scheme below, the following examples of Table 21a were prepared as described above for (S)-2-(dimethylamino)ethyl 8-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl- lH-pyrazol-l-yl)phenyl)-2,252-tnfluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3- carboxylate (Example 66a), using the appropriate alkylating agent.
Figure imgf000365_0001
Table 21a.
Figure imgf000366_0001
diazaspiro [4.5 ] decane- 3 -carboxy late
Table 21b.
NMR Data for Compounds of Table 21a
Figure imgf000366_0002
Figure imgf000367_0001
Example 67a: (S)-isopropyl 8-(2-amino-6-((R)-l-(3'>4'-diniethyl-3-(3-methyl-lH-pyrazol-l- yl)-[l,l,-biphenyI]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate
Figure imgf000367_0002
To a solution of the compound of Example lm (400 mg, 0.53 mmol) in propan-2-oi (5 mL) was added thionyl chloride (2 drops) at 0°C. The mixture was warmed to RT and then heated to reflux for 2 h. Then the reaction mixture was cooled to RT, concentrated and neutralized with saturated aqueous NaHC03 solution to pH 7-8. The aqueous layer was extracted with CH2C12. The combined organic layers were washed with brine, dried over a2S04, filtered, concentrated in vacuo and purified by flash column (0-10% MeOH in DCM) on silica gel to afford the title compound as a white solid.
Ή NMR (400 MHz, MeOH-d4): δ ppm 7.96 (d, J = 2.3 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.70 (dd, J = 8.2, 1.8 Hz, 1H), 7.59 (d, J = 1.8 Hz, 1H), 7.43 (s, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.19 (d, J - 8.0 Hz, 1H), 6.76 (q, J = 6.8 Hz, IH), 6,41 (d, J = 2.3 Hz, IH), 5.74 (s, 1H), 5.01 (m, IH), 3.76 (dd, J = 8.7, 7.0 Hz, IH), 3.61 - 3.42 (m, 4H), 2.88 (d, J = 1 1.1 Hz, IH), 2.72 (d, J = 11.0 Hz, IH), 2.39 (s, 3H), 2.31 (s, 3H), 2.29 (s, 3H)} 2.05 (dd, J - 13.1 , 8.9 Hz, IH), 1.71 (dd, J = 13.0, 7.0 Hz, IH), 1.50 (m, 4H), 1.24 (dd, J = 6.2, 3.9 Hz, 6H). LCMS (MH+): 679.
Applying the generic scheme below, the following examples of Table 22 were prepared as described above for (S)-isopropyl 8-(2-amino-6-((R)-l-(3',4,-dimethyl-3-(3-methyl-lH-pyrazol- l-yl)-[l,r-biphenyi]-4-yl)-2,2,2-trifluoroe
carboxylate (Example 67a), using the appropriate alcohol.
Figure imgf000368_0001
Table 22a.
Figure imgf000368_0002
Table 22b.
NMR Data for Compounds of Table 22
NMR No.
Ή NMR (400 MHz, MeOH-d4): δ ppm 7.96 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.71 (dd, J = 8.2, 1.8 Hz, 1H), 7.60 (d, J = 1.7 Hz, 1H), 7.44 (s, 1H), 7,37 (dd, J = 7.9, 1.9 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 6.76 (q, J = 6.9 Hz, III), 6.41 (d, J = 2.3 Hz,
67b
1H), 5.74 (s, 1H), 5.21 - 5.14 (m, 1H), 3.76 (dd, J = 8.8, 6.9 Hz, 1H), 3.61 - 3.42 (m, 4H), 2.88 (d, J = 11.0 Hz, 1H), 2,72 (d, J = 11.0 Hz, 1H), 2.39 (s, 3H), 2.31 (s, 3H), 2,28 (s, 3H), 2,04 (dd, J = 13.1, 8.8 Hz, 1H), 1.87 (d, J = 7.3 Hz, 2H), 1.77 - 1.56 (m, 7H), 1.50-1.45 (m, 4H)
Ή NMR (400 MHz, MeOH-d4): δ ppm 7.96 (d, J = 2.3 Hz, 1H), 7,76 (d, J = 8,3 Hz, lH), 7.71 (dd, J = 8.2, 1.6 Hz, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.44 (s, 1H), 7.37 (dd, J = 7.8, 1.6 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1H), 6.76 (q, J - 6.5 Hz, 1H), 6.41 (d, J = 2,3 Hz,
67c
1H), 5.74 (s, 1H), 3.83 (t, J = 8,0 Hz, 1H), 3.71 (s, 3H), 3.61 - 3.41 (m, 4H), 2.86 (d, J = 1 1.0 Hz, 1H), 2.74 (d, J = 1 1.0 Hz, 1H), 2.39 (s, 3H), 2.31 (s, 3H), 2.28 (s, 3H), 2.06 (dd, J = 13.0, 8.7 Hz, 1H), 1.72 (dd, J = 13.0, 7.2 Hz, 1H), 1.55 - 1.43 (m, 4H)
¾ NMR (400 MHz, MeOH-d4): δ ppm 0.95 (m, 3H), 1.49 (dt, J = 12.0, 6.0 Hz, 4H), 1.69 (m, 3H), 2.06 (dd, J = 13.1 , 8.8 Hz, 1H), 2.29 (d, J = 10.3 Hz, 6H), 2.39 (s, 3H), 2.73 (d, J = 1 1.0 Hz, 1H), 2.87 (d, J = 1 1.0 Hz, 1H), 3.30 (m, 4H), 3,51 (dt, J = 27.9, 6.6
67d
Hz, 4H), 3.81 (dd, J = 8.7, 7,1 Hz, 1H), 4.08 (m, 2H), 5.74 (s, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.76 (q, J = 6.7 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 7.40 (m, 2H), 7.59 (d, J = 1.8 Hz, 1H), 7.72 (m, 2H), 7.96 (d, J = 2,4 Hz, 1H)
Example 68a: (S)-isopropyl 8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4'-isopropoxy-3-(3-methyl- lH-pyrazol-l-yI)-[l,l'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yi)-2,8-diazaspiro[4.5]decane-3- carboxylate
Figure imgf000369_0001
The title compound was prepared as described for (S)-isopropyl 8-(2-amino-6-((R)-l-(3',4'- dimethy]-3-(3-methyl-lH-pyrazol-l-yl)-[l, -biphenyl] -yl)-2,2;2-trifluoroethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (Example 67a) starting with (S)-8-(2-amino-6-((R)- 2,2,2-trifluoro- 1 -(4'-isopropoxy-3-(3-methyl-l H-pyrazol- 1 -yl)-[l ,l'-biphenyl]-4- yl)ethoxy)pyrimidin-4-yI)-2,8-diazaspii [4.5]decane-3-carboxylic acid (Example 1). Applying the generic scheme below, the following examples of Table 23 were prepared as described above for (S)-isopropyl 8-(2-amino-6-((R)-2,2,2-trifluoiO-l-(4'-isopi poxy-3-(3- inethyl-lH-pyrazol-l-yl)-[l,r-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspivo[4,5]decane- -carboxylate (Example 68a), using the appropriate alcohol.
Figure imgf000370_0001
Table 23a.
Table 23b.
NMR Data for Compounds of Table 23
Figure imgf000370_0003
5.75 (s, 1H), 6.40 (d, J = 2.4 Hz, 1H), 6.75 (q, J = 6.6 Hz, 1H), 6.97 (m, 2H), 7.59 (m, 3H), 7.71 (m, 2H), 7.95 (d, J = 2.4 Hz, 1H)
Ή NMR (400 MHz, MeOH-d4): δ ppm 0.94 (t, J = 7.4 Hz, 3H), 1.32 (d, J = 6.0 Hz, 6H), 1.50 (dt, J = 12.3, 6.0 Hz, 4H), 1.69 (m, 3H), 2.07 (dd, J = 13.1, 8.8 Hz, 1H), 2.39 (s, 3H), 2.73 (d, J = 1 1.0 Hz, III), 2.88 (d, J = 1 1.0 Hz, 1H), 3.52 (dp, J = 20.9, 7.5 Hz,
68c
4H), 3.81 (dd, J = 8.7, 7.1 Hz, 1H), 4.09 (m, 2H), 4.64 (h, J = 6.0 Hz, 1H), 5.74 (s, IH), 6.40 (d, J = 2.4 Hz, 1H), 6.76 (q, J - 6.7 Hz, 1H), 6.96 (m, 2H), 7.58 (m, 3H), 7.71 (m, 2H), 7.95 (d, J = 2.4 Hz, 1H)
Example 69a: (S)-isopropyl 8-(2-amino-6-((R)-l-(5-ch]oro-[l,l'-biphenyI]-2-yl)-2,2,2- trifluorocthoxy)pyrimidi -4-yl)-2,8-diazaspiro[4.5]decane-3-carboxyIate
Figure imgf000371_0001
The title compound was prepared as described for (S)-isopropyl 8-(2-amino-6-((R)-l-(3'}4'- dimethyl-3-(3-methyl- lH-pyrazol-1 -yl)-[l } -biphenyl]-4-yl)-2,2,2-trifluoi'oethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (Example 67a) starting with (S)-8-(2-amino-6-((R)- l 5-chloro-[l ,l'-biphenyl]-2-yl)-2,2,2-trifluoiOethoxy)pyrimidin--4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid (Example 34c).
Applying the generic scheme below, the following examples of Table 24 were prepared as described above for (S)-isopropyl 8-(2-amino-6-((R)-2,2,2-trifluoro-l -(4,-isopropoxy-3-(3- methyl-l H-pyrazol-l-yl)-[l, -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane- -carboxylate (Example 68a), using the appropriate alcohol.
Figure imgf000371_0002
Table 24a.
Figure imgf000372_0001
Table 24b.
NMR Data for Compounds of Table 24
Figure imgf000372_0002
Example 70: (S)-methyl 8-(2-amino-6-((R)-l-(5-chloiO-3'-(methyIsulfonyl)-[l,l'-biphenyl]- 2-yl)-2,2,2-triflxioiOethoxy) rimidin-4-yl)-2,8-diazaspiro[4.5]decaiie-3-carboxylate
Figure imgf000373_0001
The title compound was prepared as described for (S)-isopropyl 8-(2-amino-6-((R)-l -(3',4'- dimethyl-3-(3-methyl-lH-pyrazol-l-yl)-[l,r-biphenyl]-4-yl)-2,2,2-trifluoiOethoxy)pyrimidi yl)-2,8-diazaspii'o[4.5]decane-3-carboxylate (Example 67a) starting with (S)-8-(2-amino-6-((R)- l-(5-chloi -3'-(methylsulfonyl)-[l Jl '-biphenyl]-2-yl)-2)2,2-trifluoi ethoxy)pyiirnidin-4-yl)-2,8- diazaspiiO[4.5]decane-3-carboxylic acid (Example 34w). 'H NMR (400 MHz, MeOH-d4): δ ppm 1.51 (q, J = 7.1 , 6.7 Hz, 6H), 1.72 (dd, J = 13.0, 7.3 Hz, 1H), 2.07 (dd, J = 13.2, 8.7 Hz, 1H), 2.75 (d, J = 11.0 Hz, 1H), 2.87 (d, J = 11.0 Hz, 1H), 3.21 (s, 4H), 3.50 (tdt, J = 20.3, 13.5, 7.0 Hz, 4H), 3.71 (s, 2H), 3.84 (t, J = 8.0 Hz, 1H), 4.87 (m, 1H), 5.57 (s, 1H), 6.57 (q, J = 6.6 Hz, 1H), 7.33 (d, J = 2.3 Hz, 1H), 7.41 (s, 2H), 7.48 (dd, J = 8.5, 2.2 Hz, 1H), 7.75 (m, 3H), 8.07 (d, J = 7.8 Hz, 1H), 8.43 (s, 1H). LCMS (MPI+): 655.
Example 71: (S)-methyl 8-(2-amino-6-((R)-l-(5-chloro-3*-sulfamoyl-[l,r-biplicnyI]-2-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane~3-carboxylate
Figure imgf000373_0002
The title compound was prepared as described for (S)-isopropyl 8-(2-amino-6-((R)-l-(3',4'- dimethyi-3-(3-methyl-lH-pyrazol-l -yl)-[l)r-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyi½iidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (Example 67a) starting with (S)-8-(2-amino-6-((R)- 1 -(5-chloiO-3'-sulfamoyl-[ 1 , l'-biphenyl]-2-yl)-2>2!2-trifluoiOethoxy)pyrimidin-4-yl)-2)8- diazaspiro[4.5]decane-3-carboxylic acid (Example 34u). Ή N R (400 MHz, MeOH-d4): 8 ppm 1.54 (dt, J = 8.9, 6.0 Hz, 5H), 1.75 (dd, J = 13.1 , 7.4 Hz, lH), 2.10 (dd, J = 13.1, 8.7 Hz, 1H), 2.77 (d, J = 11.0 Hz, 1H), 2.89 (d, J = 1 1.0 Hz, 1H), 3.53 (qt, J = 14.0, 7.8 Hz, 4H), 3.72 (s, 3H), 3.86 (dd, J = 8.7, 7.3 Hz, 1H), 4.91 (s, 13H), 5.57 (s, ΪΗ), 6.60 (q, J = 6.5 Hz, 1H), 7.31 (d, J = 2.2 Hz, 1H), 7.49 (dd, J = 8.5, 2.3 Hz, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.71 (m, 2H), 8.02 (ddd, J = 7.9, 1.9, 1.1 Hz, 1H), 8.33 (s, 1H). LCMS (MH+):656. LCMS (MH+): 656.
Example A; In vitro Inhibition Assays
TPHl and TPH2 Assays
Recombinant human TPHl (rTPHl GenBank TM accession no. NP_004179) was expressed by cloning full length human TPHl cDNA in to a bacterial pMAL-c5E expression vector to produce maltose-binding protein (MBP) TPHl fusion proteins. E.coli BL21 (DE3) containing pM AL-c5E-TPHl was used for protein generation and the recombinant protein was purified utilizing standard column chromatography techniques. The MBP tagged TPHl (MBP- TPH1) was used directly to screen compounds as described below. Recombinant human TPH2 (rTPH2 GenBank TM accession no. 173353), PheOH (rPheOH GenBank TM accession no. K03020) and TH (rTH GenBank TM accession no. L20679) with an MBP tag were produced similarly.
TPHl activities were measured in an assay containing 200 mM ammonium sulfate, 7 ffiM DTT, 50 ^tg/mL catalase, 25 μΜ ammonium iron sulfate, 50 mM MES, pH 7.1. Test compounds were diluted in 100% DMSO and added to the assay plate in 1 μΕ aliquots at lOOx final concentration, Fifty microliters of assay buffer containing 30 nM TPHl enzyme (MBP tagged) were added to the plate wells containing the test compound by the use of an Eppendorf repeater pipette. The reaction was initiated by the addition of 50 μΕ of assay buffer containing 60 μΜ tryptophan and 72 μΜ 6-6-methyltetra-hydropterin (2x final concentration) by the use of a Multidrop (LabSystems). Final reaction conditions were 15 nM TPHl enzyme, 30 μΜ tryptophan, 36 μΜ 6-methyltetra-hydi pterin, 200 mM ammonium sulfate, 7 mM DTT, 25 ^ig/mL catalase, 25 μΜ ferrous ammonium sulfate, 50 mM MES, pH 7.1, with atmospheric oxygen at room temperature. The plate was immediately placed onto an M5 plate reader (Molecular Devices) for kinetic fluorescence measurement using an excitation setting of 300 nm and an emission setting of 335 nm. Fluorescence reads are recorded in kinetic mode for 300 seconds (5 minutes).
Kinetic assay data for compounds at specific concentrations was translated into slopes using the Softmax Pro software on a Spectramax reader, and compound inhibition slopes were compared with wells containing enzyme, substrate and cofactor in the absence of inhibitor (100%), and wells containing substrate and cofactor in the absence of enzyme (0%). DMSO concentration in the assay was 1%. Typically, in the absence of enzyme, reaction slopes were -0. ICso's were determined using Graphpad Prism.
Compounds having an IC50 of 10,000 nM or less were considered active.
Inhibition of TPH2 activity by the compounds of the invention was measured similarly. In some instances, compounds of the invention showed dual inhibition of both TPHl and TPH2.
Data related to TPHl inhibition activity of the compounds of the invention is provided below in Table 25. Compounds that inhibit TPHl with an IC50 from 3,000 nM to 10,000 nM are indicated by +. Compounds that inhibit TPHl with an IC50 of less than 3,000 nM but more than 300 nM are indicated by ++, Compounds that inhibit TPHl from 50 nM to 300 nM are indicated by +++, Compounds that inhibit TPHl with an IC50 less than 50 nM are indicatead by ++++. Ester prodrugs listed, for example, in Tables 18a, 19a, 20a, and 21 a-24a, as well as in Examples 70 and 71, are not expected to be active in this in vitro assay.
Table 25. TPHl Inhibition Data
Figure imgf000375_0001
Figure imgf000376_0001
Figure imgf000377_0001
Figure imgf000378_0001
PheOH and TH inhibition counter assays
Certain compounds of the Examples were found to inhibit tryptophan hydroxylase (TPH) selectively over phenylalanine hydroxylase (PheOH), Inhibitory activity against PheOH can be assessed according to the methods described for example in J. Med. Chem. 10, 64-66 ( 967), or J Antibiot. 35, 458-462 (1982), or WO 2007/089335.
Certain compounds of the invention were found to inhibit tryptophan hydroxylase (TPH) selectively over tyrosine hydroxylase (TH). Inhibitory activity against TH can be assessed according to the methods described for example in Life Sci. 39, 2185-2189 (1986), or Mol Pharmacol. 41, 339-344 (1992), or J Antibiot. 35, 458^162 (1982), or WO 2007/089335. Example B: Intestinal 5-HT depletion assay
The efficacy of the TPH1 inhibitors of the invention was assessed for the ability to decrease intestinal serotonin concentration in mice. Mice (C57 BL6) were administered a single 150 mg/kg dose of test article by oral gavage. Each animal was euthanized by exsanguination under isoflurane anesthesia. Jejunal intestinal mucosa was isolated and homogenized in 300 μ of a buffer containing 0.3M trichloroacetic acid, 0.1M sodium acetate, 10 mM EDTA, 20 mM sodium bisulfate and 50 mM ascorbic acid. Following centrifugation the 5-HT levels in the supernatants were measured by HPLC. The remaining mucosal pellet was solubilized overnight at 37 °C in a 0.1 % sodium dodecyl sulfate buffer in 0. IN NaOH followed by determination of protein concentrations using a BCA protein assay (Pierce, Rockford, II. 5-HT levels were normalized to protein and data were expressed as mean percent reduction of mucosal 5-HT levels relative to vehicle control ± SEM (percent 5-HT reduction). All animal studies were carried out with protocols approved by the Institutional Animal Care and Use Committee.
The Examples listed in Table 26 below were tested and found to elicit a reduction in mean mucosal 5-HT concentrations relative to vehicle-treated animals according to the above- described in vivo assay, P-values, indicating statistical significance of the data (ANOVA) are provided in the table: * refers to P<0.05, ** refers to P<0.01, *** refers to PO.005, and **** refers to PO.0005.
Table 26. In Vivo Efficacy of TPH1 Inhibitors In Mice (reduction of mucosal 5-HT concentrations one day after oral administration of a single 150 mg/kg dose)
Figure imgf000379_0001
Figure imgf000380_0001
Example C: Reduction of mucosal 5-HT concentrations
The Examples listed in Table 27 below were tested and found to elicit a reduction in mean mucosal 5-HT concentrations relative to vehicle-treated animals according to the following in vivo assay.
The efficacy of the TPH1 inhibitors of the invention was assessed for the ability to decrease intestinal serotonin concentration in mice. Mice (C57 BL6) were administered an oral dose of 10 or 50 mg/kg of the test article in the evening. Approximately 16 h following the first dose, mice were administered a second oral dose of 50 mg kg of the appropriate compound. A third oral dose of 50 mg/kg of the appropriate test article was administered 12 h after dose 2. Following an overnight fast, each animal was euthanized by exsanguination under isoflurane anesthesia. Jejunal intestinal mucosa was isolated and homogenized in 300 mL of a buffer containing 0.3M trichloroacetic acid, 0.1M sodium acetate, 10 mM EDTA, 20 mM sodium bisulfate and 50 mM ascorbic acid. Following centrifugation the 5-HT levels in the supernatants were measured by HPLC. The remaining mucosal pellet was solubilized overnight at 37 °C in a 0.1% sodium dodecyl sulfate buffer in 0. IN NaOH followed by determination of protein concentrations using a BCA protein assay (Pierce, Rockford, IL). 5-HT levels were normalized to protein and data were expressed as mean percent reduction of mucosal 5-HT levels relative to vehicle control ± SEM (percent 5-HT reduction). All animal studies were carried out with protocols approved by the Institutional Animal Care and Use Committee. P-values, indicating statistical significance of the data (ANOVA) are provided in the table: * refers to P<0.05, ** refers to P<0.01, *** refers to PO.005, and **** refers to PO.0005.
Tabic 27. In Vivo Efficacy of TPH1 Inhibitors In Mice (reduction of mucosal 5-HT concentrations two days after oral administration of a single 50 nig/kg dose)
Figure imgf000381_0001
Example D: /// vivo assay for inflammatory bowel diseases
The utility of the compounds of the invention for the treatment of inflammatory bowel diseases can be measured, for example, using the experimental models of colitis induced by trinitiobenzene sulfonic acid (TNBS), dinitrobenzene sulfonic acid (DNBS), and dextran sodium sulfate (DSS), as described by Ghia, J.-E. et al. in Gastroenterol. 137, 1649-60 (2009).
Example E: In vivo assay for low bone mass diseases
The utility of the compounds of the invention for the treatment of low bone mass diseases, such as osteoporosis, can be measured, for example, using the ovariectomy-induced osteopenia rat model, as described by Yadav, V, K. et al. in Nature Med 16, 308-12 (2010),
Example F: In vivo assay for PAH
The utility of the compounds of the invention for the treatment of pulmonary arterial hypertension (PAH), can be measured, for example, using the hypoxia mouse model, as described by Abid, S. et al. in Am. J. Physiol., Lung Cellular and Molecular Physiology 303, L500-8 (2012), or using the rat monocrotaline-induced PAH or the rat chronic hypoxia model, as described by Kay, J. M. et al. Respiration 47, 48-56 (1985).
Example G; /// vivo assay for allergic airway inflammation
The utility of the compounds of the invention for the treatment of allergic airway inflammation, can be measured, for example, using the mouse model of allergic asthma, as described by Dikk, T. et al. in Am. J. Respir. Crit. Care Med. 187, 476^185 (2013).
Example H: /// vivo assay for gastrointestinal disorders
The utility of the compounds of the invention for the treatment of gastrointestinal disorders associated with dysregulation of the GI serotonergic system, such as chemotherapy- induced emesis and irritable bowel syndrome, can be measured, for example, using the a ferret model of chemotherapy-induced emesis, as described by Liu, Q. et al. in J. Pharmacol. Exp. Ther. 325, 47-55 (2008).
Example I: In vivo assay for tumor growth
The utility of the compounds of the invention for the treatment of tumor growth, can be measured, for example, using the the xenograft model of cholangiocarcinoma tumor growth, as described by Alpini, G. et al. in Cancer Res. 68, 9184-93 (2008). Example J: In vivo assay for leukemia
The utility of the compounds of the invention for the treatment and prevention of leukemia and other cancers of the blood, can be measured, for example, using the mouse leukemia model, the osteoblast- deficient mouse model, or the murine model of acute myeloid leukemia, as described in WO 2013/074889.
Example : In vivo assay for atherosclerosis
The utility of the compounds of the invention for the treatment of atherosclerosis, and the reduction of plasma cholesterol and triglyceride levels, can be measured, for example, using the Apo E -/- or LDLR -/- mouse models of atherosclerotic plaque development, as described in WO 2012/058598,
Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patent, patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety.

Claims

What is claimed is:
1. A compound of Formula I:
Figure imgf000384_0001
I
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is C3-io cycloalkyl, Ce-ioaryl, 4 to 10-membered heterocycloalkyl, or 5 to 10- membered heteroaryl;
L is O or NR4;
W is N or CR5;
X is N or CR6;
Y is N or CR7;
wherein only one of X and Y is N;
R1 is H, Ci-io alkyl, C3-tocycloalkyl, phenyl, -(CR8R9)pOC(O)R,0 ; -(C ^p R^R12 , or
Figure imgf000384_0002
wherein said Cj-io alkyl, C3.!o cycloalkyl, and phenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from F, CI, Br, CN, Ci-4 alkyl, and C|.4 haloalkyl;
R2 and R3 are each independently selected from H, CM alkyl, and CM haloalkyl;
R4 is H or CM alkyl;
R5 and R6 are each independently selected from H, halo, and C alkyl;
R7 is H, CM alkyl, C2-6 alkenyl, C3-io cycloalkyl, Qj-io cycloalkyl-CM alkyl, Ce-ioaryl, C6- io aryl-Ci-4 alkyl, 4- 10 membered heterocycloalkyl, (4- 10 membered heterocycloalkyl)-Ci-4 alkyl, 5-10 membered heteroaryl, (5-10 membered heteroaryl)-Ci.4 alkyl, NR13R14, OR15, C(0)R16, S(0)qR17, wherein said C alkyl, C2-6 alkenyl, C3.iocycloalkyl, C3-io cycloalkyl-Ci-4 alkyl, Ce-ιο aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)- Ct-4 alkyl, 5-10 membered heteroaryl, and (5- 10 membered heteroaryl)-Ci -4 alkyl are each optionally substituted by 1 , 2, or 3 substituents selected from halo, C alkyl, Ci-e alkenyl, amino, Ct-4 alkylamino, C2-8 dialkylamino, hydroxy, and Ci-4 a!koxy;
R8 and R9 are each independently selected from H and Ci-4 alkyl;
Ri0 is Ci-6 alkyl optionally substituted by 1, 2 or 3 substituents independently selected from Ci-6 haioalkyl, C3.io cycloalkyl, ORa, and NRcRd;
R1 1 and R12 are each independently selected from H and Ci-6 alkyl;
Rl3 is H or Ci.4 alkyl;
R14 is H, C M alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-Ci-4 alkyl, C6-io aryl, Ce-io ar l-C alkyl, 4-10 membered heterocycloalkyl, (4-10 memberedheterocycloalkyl)-Ci-4 alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl)-Ci-4 alkyl, C(0)Rbl, C(0)ORal,
C(0)NRcIRd l, S(0)Rbl s S(0)2Rbl, or S(0)2NRc!Rdi , wherein said CM alky!, C3-7 cycloalkyl, C3.7 cycloalkyl-C alkyl, Cg-io aryl, C6-iQ aryl-Ci-4 alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)~Ci-4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)- C 1-4 alkyl are each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, C M alkyl, CM haioalkyl, CN, N02, ORal, SRai , C(0)Rbl, C(0)NRclRdi, C(0)ORal, OC(0)RbI , OC(0)NRctRdl, NRCIRdl, NRclC(0)Rbl, NRolC(0)ORal,
NRclC(0)NRc,Rdl, NRclS(0)Rbl 5 NRc,S(0)2RbI , NRclS(0)2NRclRdl , S(0)Rbl, S(0)NRctRdl, S(0)2Rb l, and S(0)2NRclRdi ;
or R13 and R14 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7- membered heterocycloalkyl group optionally substituted with 1 , 2, or 3 substituents
independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, 5-6 membered heteroaryl, halo, CN, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl, OC(0)NRc]Rdl, NR0lRdl s NRclC(0)Rbl , NRc,C(0)NRclRdI, NRclC(0)ORal, S(0)Rbl , S(0)NRc!Rdt, S(0)2Rbl, NRctS(0)2Rbl, NRclS(0)2NRclR l, and S(0)2NRc!Rdl, wherein said Cj-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, CN, ORal , SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORnl, OC(0)Rbl,
OC(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRc, C(0)ORaE, S(0)Rbl,
S(0)NRc!Rd! , S(0)2RB L , NRclS(0)2Rbl, NRcIS(0)2NRclR I, and S(0)2NRclRdl ; R!5 is H, Ci-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C alkyl, C6.io ryl, Ce-io aryl-Ci^ alkyl, 4- 10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl)-Ci-4 alkyl, wherein said C alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-Ci-4 alkyl, Ce-io aryl, Ce-ioaryl-CM alkyl, 4-10 membered
heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-Ci.4 alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3 -7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, 5-6 membered heteroaryl, CN, ORal, SRal, C(0)Rbl, C(0)NRcIRdt, C(0)ORat, OC(0)Rbl,
OC(0)NRc!Rdl, NRcIRdl, NR0lC(O)Rbl, NRc!C(0)NRclRdl, NRclC(0)ORaI, S(0)RbI,
S(0)NRciRdI, S(0)2Rbl, NRc!S(0)2Rb!, NRclS(0)2NRctRdI, and S(0)2NRclRd!;
R16 is Ci- alkyl or NR18aR18b wherein said CM alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, 5-6 membered heteroaryl, CN, ORal, SRaI, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl, OC(0)NRc,Rdl, NRcIRdl, NRclC(0)Rbl, NRclC(0)NRclRdt, NRclC(0)ORal, S(0)Rbl, S(0)NRclRd), S(0)2Rb!, NRclS(0)2RbI, NRCIS(0)2NRclRdl ) and S(0)2NRclRdl ;
R17 is CM alkyl, NR1SaR18 , or OR18c, wherein said CM alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, 5-6 membered heteroaryl, CN, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl, OC(0)NRclRdl, NRclRd,, NRc,C(0)Rbl, NRclC(O)NR0lRdl,
NRclC(0)ORal, S(0)R l, S(0)NRclRd[, S(0)2Rbi, NR0[S(O)2Rbl, NRc,S(0)2NRclRdl, and S(0)2NRclRdl;
Rl8a and R18b are each independently selected from H and C alkyl wherein said C alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-ioaryl, 5-6 membered heteroaryl, CN, ORal, SRal, C(0)Rb!, C(0)NRclRdl, C(0)ORal, OC(0)Rbl, OC(0)NRclRdl, NRclRdi, NRclC(0)Rbl, NRclC(0)NRclRdl, NRc4C(0)ORal, S(0)Rbl, S(0)NRclRdI, S(0)2Rbl, NR0lS(O)2Rbl,
NRc!S(0)2NRc,RdI, and S(0)2NRclRdl;
or R18a and Rl8b together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryi, 5-6 membered heteroaryl, halo, CN, ORa], SRal, C(0)Rbl, C(0)NRclRdI, C(0)ORal, OC(0)Rb!, OC(0)NRcIRd!, NRc!Rdl, NRc,C(0)RbI, NR0,C(O)NRclRdl, NRc!C(0)ORal,
S(0)Rbl, S(0)NRclRd\ S(0)2Rb,, NRc,S(0)2Rbl, NRclS(0)2 RclRdI. and S(0)2NRclRdl, wherein said Ci.6 alkyl, C3-7 cycioalkyl, 4-7 membered heterocycloalkyl, C6-io aryl; and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)ORal, OC(0)Rbl,
OC(0)NRclRdi, NRclRdl, NRclC(0)Rbf , NRclC(0)NRclRdl, NRe]C(0)ORal, S(0)Rbl,
S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbi J NRcIS(0)2NRclRdi, and S(0)2NRclRdl;
RI8c is H} Ci-6 alkyl, C3-10 cycioalkyl, C3-7 cycloalkyI-Ci-4 alkyl, Ce-io aryl, Ce-io a yl-C alkyl, 4-10 membered heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, 5-10 membered heteroaryl, or (5-10 membered heteroaryl)-Ci-4 alkyl, wherein said Ct-e alkyl, C3-7 cycioalkyl, Cj-iocycloalkyl-C alkyl, Ce-io aryl, C6-io aryl-Ci-4 alkyl, 4-10 membered
heterocycloalkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, 5-10 membered heteroaryl, and (5-10 membered heteroaryl)-C[-4 alkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CM alkyl, CM haloalkyl, CN, N02, ORal, SRal, C(0)Rb[, C(0)NRclRdl, C(0)ORa!, OC(0)Rbi, OC(0)NRclRdI, NRc]Rdl, NRc,C(0)Rbl, NR0lC(O)ORaI, NRciC(0)NRcERd5, NRctS(0)RbI, NRclS(0)2R l, NRc,S(0)2NRclRdl, S(0)Rbl, S(0)NRcIRdl, S(0)2Rbl, and S(0)2NRclRdl;
RA is H, Cy1, halo, Ci-6 alkyl, C2.6 alkenyl, CN, NO2, OR32, SRa2, C(0)Rb2, C(0)NRc2Rd2, C(0)ORa2, OC(0)Rb2, OC(0)NRc2Rd2, NRc2Rd2, NRc2C(0)Rb2, NRc2C(0)ORa2,
NRc2C(0)NRc2Rd2, NRc2S(0)Rb2, NRc2S(0)2Rb2, NRe2S(0)2NRc2Rd2, S(0)Rb2, S(0)NRc2Rd2, S(0)2Rb2, or S(0)2NRc2Rd2, wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy1, halo, Ci-6 alkyl, C2- 6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa2, SR 2, C(0)Rb2, C(0)NRc2Rd2, C(0)ORa2, OC(0)Rb2 ; OC(0)NRc2Rd2, NRc2Rd2, NRc2C(0)Rb2, NRc C(0)ORn2, NRc2C(0)NRc2Rd2, NRc2S(0)Rb2, NRc2S(0)2Rb2, NRc2S(0)2NRc2Rd2, S(0)Rb2, S(0)NRc Rd2, S(0)2Rb2, and S(0)2NRc2Rd2;
RB is H, Cy2, halo, Ci-6 alkyl, C2.6 alkenyl, CM haloalkyl, CN, N02, OR33, SR33, C(0)Rb3, C(0)NRc3Rd3, C(0)ORa3 5 OC(0)Rb3, OC(0)NRc3Rd3, NRc3Rd3, NRc3C(0)Rb3, NRc3C(0)ORa3, NRc3C(0)NRc3Rd ; NRc3S(0)Rb3, NRc3S(0)2Rb3, NRc3S(0)2NRc3Rd3, S(0)Rb3, S(0)NRc3Rd3, S(0)2Rb3, or S(0)2NRc3Rd3, wherein said C alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy2, halo, Ci-6 alkyl, C2. 6 alkenyl, C M haloalkyl, CN, N02, ORa3, SRa3, C(0)Rb3, C(0)NRc Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc3Rd3, NRc3Rd3 } NRc3C(0)Rb3, NRc3C(0)ORa3, NRc3C(0)NRc3Rd3, NRc3S(0)Rb3, NRCIS(0)2Rb3, NRc3S(0)2NRc3Rd3, S(0)Rb3, S(0)NRc3Rd3, S(0)2Rb3, and S(0)2NRc3Rd3;
Rc and RD are independently selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6
haloalkyl, CN, N02, ORa4, SRa4, C(0)Rh4, C(0)NRc4Rd4, C(0)ORa4 ; OC(0)Rb4, OQC R^R'14, NRc Rd 3 NRc C(0)Rb ) NRc4C(0)ORa4, NR114 C (0)NRc Rd4 , NRc4S(0)Rb4, NRc S(0)2Rb4, NRc4S(0)2NRc Rd4, S(0)Rb4, S(0)NRc4Rd4, S(0)2RM, and S(0)2NRc4Rd4; wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C6-jo aryl, Cs-io cycloa!kyl, 5-10 membered heteroaryl, 4-10 membered
heterocycloalkyl, halo, C|.6 alkyl, C2.6 alkenyl, C[-6 haloalkyl, CN, N02) ORa4, SRa4, C(0)Rb4, C(0)NRc4Rd4, C(0)ORa } OC(0)Rb4, OC(0)NRe4Rd4, NR^4, NR^CC^4, NRc4C(0)ORa4 5 NRc C(0)NRc4Rd4, NRc4S(0)Rb4, NRc S(0)2Rb4 ) NRc4S(0)2NRc4Rd4, S(0)Rb+, S(0)NRc4Rd4, S(0)2Rfa4 5 and S(0)2NRc4Rd4;
Cy1 and Cy2 are each independently selected from Cg-io aryl, C3-iocycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy;
each RCy is independently selected from halo, Ci-6 alkyl, Cj-e haloalkyl, C2.6 alkenyl, C6-io aryl, Cj-io cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, N02, OR35, SRa5, C(0)Rb5, C(0)NRc5Rds, C(0)ORa5, OC(0)Rb5, OC(0)NRc5Rd5, NRc5Rd5,
NRc5C(0)R 5 ; NRc5C(0)ORa5, NRc5C(0)NRc5Rd5, NRcSS(0)Rbs, NRc5S(0)2Rb5,
NRc5S(0)2NRc5Rds, S(0)RbS, S(0)NRc5Rd5, S(0)2Rbs, and S(0)2NRc5Rd5, wherein said Ci-6 alkyl, C2-6 alkenyl Ce- 10 aryl, C3-io cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, CN, N02, ORaS, SRaS, C(0)Rbs, C(0)NRc5Rd5, C(O)0Ra5, OC(0)Rb5, OC(0)NRc5Rd5, NRc5Rd5, NRc5C(0)Rb5, NRc5C(0)ORa5, NRc5C(0)NRc5Rd5,
NRc5S(0)Rb5, NRc5S(0)2Rbs, NRc5S(0)2NRc5Rd5, S(0)Rb5 ; S(0)NRc5Rd5, S(0)2Rb5, and
S(0)2NRc5Rd5;
each Ra, RaI, Ra2, R"3, Ra4, and Ra5 is independently selected from H, Ci-6 alkyl, C1.4 haloalkyl, C2.6 alkenyl, C6-io ryl, C3-io cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl-Ci-4 alkyl, C3-io cycloalkyl-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci. 4 alkyl, or (4-10 membered heterocycloalkyl)-Ci-4 alkyl, wherein said Ci-e alkyl, C2-6 alkenyl, C6- 10 aryl, C3-io cycloaIkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-io aryl- Ci-4 alkyl, C3-io cycloaJkyl-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, and (4-10 membered heterocycloalkyl)-C alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from CM alkyl, halo, CN, ORa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6 5 OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc5C(0)Rb6, NRc6C(0)NRc6Rd6,
NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6 ; NRc6S(0)2R 6, NRc6S(0)2NRc6Rd6, and S(0)2NR(6R 6;
each Rbl, R 2, Rb3, RM, and Rb5 is independently selected from H, Ci-6 alkyl, CM
haloalkyl, C2-6 alkenyl, C6-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-io ai l-Ci^ alkyl, C3-io cycloalkyl-CM alkyl, (5-10 membered heteroaiyl)-Ci- 4 alkyl, or (4-10 membered heterocycloalkyl)-Ci-4 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C6- 10 aryl, C3-to cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl- C 1-4 alkyl, C3-10 cycloalkyl-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, and (4-10 membered heierocycloalkyl)-C 1-4 alkyl are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from CM alkyl, halo, CN, ORa6 5 C(0)Rb6, C(0)NRc6Rd6, C(0)OR"6, OC(0)Rbf\ OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6,
NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
each Rc , Rd, Rcl, RdI, Rc2, Rd2, Rc3, Rd3, R04, R 4, RcS, and Rd5 is independently selected from H, Ct-6 alkyl, Cj .4 haloalkyl, C2-6 alkenyl, Ce-io aryl, C3.10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-io aryl- C 1-4 alkyl, C3-io cycloalkyl-Ci-4 alkyl, (5- 10 membered heteroaryl)-Cj.4 alkyl, or (4-10 membered heterocycloalkyl)-Ci-4 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C6-]o aryl, C3.10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-ioaryl-CM alkyl, C3-10 cycloalkyl-C[.4 alkyl, (5-10 membered heteroaryl)-Ci.4 alkyl, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C alkyl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRe6Rd6,
NRc6C(0)R 6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6 ; S(0)NRc6Rd6, S(0)2Rb6,
NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci.6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, 5-6 membered heteroaryl, halo, CN, ORa6, SRa6, C(0)Rb6 5 C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6 5 NRc6Rd6, NRc6C(0)Rh6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6 }
S(0)Rbf>, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said Ci-e alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-to aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRo6Rd6, NRc6Rd6} NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRcfiRd6, S(0)3Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rcl and Rdl together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci.6 alkyl, C3.7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-to aryl, 5-6 membered heteroaryl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb s NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said Ci-6 alkyl, C3 -7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6,
OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)R 6, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6,
S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any R°2 and Rd2 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Cn¾ alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, and 5-6 membered heteroaryl, Ci-e haioalkyl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NR 6C(0)Rb6, NRc6C(0)NRc6Rd6,
NRc6C(O)0Ra6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRe6S(0)2Rb6, NRc6S(0)2NRe6Rd6, and S(0)2NRc6R 6, wherein said Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, CN, ORa6, SRn6, C(0)Rb6, C(0)NRc6R 6, C(0)ORa6,
OC(0)Rb6 ; OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rbfi, NRc6C(0)NRc6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2R 6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6; or any Rc3 and Rd3 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7 -membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3.7 cycloalkyl, 4-7 membered heterocycloalkyl, Ce-io aryl, 5-6 membered heteroaryl, Ci-e haloalkyl, halo, CN, ORa6 } SRa6, C(0)R 6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6 ; OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6,
NRc6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6 } NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRe6Rd6, wherein said Ci-6 alkyl, C3.7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRe6Rd6, NRc6C(0)ORa6, S(0)Rb6, S(0)NRe6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6, and S(0)2NRc6Rd6;
or any Rc4 and Rd4 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, 5-6 membered heteroaryl, Ci-6haloalkyl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6,
NRc6C(0)ORa6, S(0)Rb6, S(0)NRe6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc S(0)2NRc6Rd6, and S(0)2NRc6Rd6, wherein said Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(0)Rb6 J C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6, NRe6C(0)ORa6, S(0)Rb6, S(0)NRc6Rd6, S(0)2Rb6, NRc6S(0)2Rb6, NRc6S(0)2NRc6Rd6 } and S(0)2NRc6Rd6;
or any Rc5 and Rd5 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-io aryl, 5-6 membered heteroaryl, Ci-ehaloalkyl, halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)Rb6, OC(0)NRc6Rd6, NRc6Rd6, NRc6C(0)Rb6, NRc6C(0)NRc6Rd6,
NRc6C(0)ORa6, S(0)Rb6 5 S(0)NRc6Rd6, S(0)2R fi, NRc6S(0)2R 6, NRc6S(0)2NRc6Rd6, and S(0)2NRc Rd6, wherein said Ci-6 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C6-to aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, ORa6, SRa6, C(0)Rb6, C(0)NRc6Rd6, C(0)ORa6, OC(0)RB6, OC(0)NRC6RD6, NRC6RD6, NRC6C(0)RB6, NRC6C(0)NRC6RD6, NRC6C(0)ORA6, S(0)RBFI, S(0)NRC6RD6, S(0)2RB6, NRC6S(0)2RB5, NRC6S(0)2NRC6RDFI, and S(0)2NRC6RD6;
each RA5, RB6, RC6 5 and RD6 is independently selected from H, C|.4 alkyl, C2-4 alkenyl, C3-7 cycloaikyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein said Ci-4 alkyl, C2-4 alkenyl, C3-7 cycloaikyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-4 alkyl, CM alkoxy, C alkylthio, C alkylamino, and di(CM alkyl)amino;
n is 1 or 2;
p is 1, 2, or 3; and
q is 1 or 2;
wherein any aforementioned 4-10 or 4-7 membered heterocycloalkyl group optionally comprises
1. 2, or 3 oxo substituents, wherein each oxo substituent that is present is substituted on a ring- forming carbon, nitrogen, or sulfur atom of the 4-10 or 4-7 membered heterocycloalkyl group,
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is 0.
3. The compound of claim 1 , or a pharmaceutically acceptable s lt thereof, wherein L is NR4.
4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein W is CR5; X is N; and Y is CR7.
5. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein W is N; X is N; and Y is CR7.
6. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein W is CR5; X is CR6; and Y is N.
7. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein W is CR5; X is CR6; and Y is CR7.
8. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein W is N; X is CR6; and Y is CR7.
9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R2 is H and R3 is H,
10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R2 is H and R3 is C alkyl.
1 1. The compound of any one of claims 1 -8, or a pharmaceutically acceptable salt thereof, wherein R2 is H and R3 is methyl.
12. The compound of any one of claims 1 -8, or a pharmaceutically acceptable salt thereof, wherein R2 is H and R3 is Cj. haloalkyl.
13. The compound of any one of claims 1 -8, or a pharmaceutically acceptable salt thereof, wherein R2 is H and R3 is trifluoromethyl.
14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein n is 1.
15. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein n is 2.
16. The compound of any one of claims 1- 15, or a pharmaceutically acceptable salt thereof, wherein Rl is H.
17. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R1 is CM0 alkyl, Cs-iocycloalkyl, phenyl, -(CR8R9)POC(0)R10, -(CRSR9)P R! 1R12 , or -(CR8R9)pC(0)NR"Ri2, wherein said Cj.jo alkyl, C3-io cycloalkyi, and phenyl are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from F, CI, Br, CN, C alkyl, and Ci-4 haloalkyi.
18. The compound of any one of claims 1 -1 5, or a pharmaceutically acceptable salt thereof, wherein R! is CMO alkyl.
1 . The compound of any one of claims 1 and 3- 8, or a pharmaceutically acceptable salt thereof, wherein R4 is H.
20. The compound of any one of claims 1 -4 and 6- 19, or a pharmaceutically acceptable salt thereof, wherein R5 is II.
21. The compound of any one of claims 1-3 and 6-20, or a pharmaceutically acceptable salt thereof, wherein R6 is H.
22. The compound of any one of claims 1 -5 and 7-20, or a pharmaceutically acceptable salt thereof, wherein R7 is other than H.
23. The compound of any one of claims 1 -5 and 7-20, or a pharmaceutically acceptable salt thereof, wherein R7 is CM alkyl, NR13R14, or OR15.
24. The compound of any one of claims 1 -5 and 7-20, or a pharmaceutically acceptable salt thereof, wherein R7 is NR!3R14,
25. The compound of any one of claims 1 -5 and 7-20, or a pharmaceutically acceptable salt thereof, wherein R7 is NH2.
26. The compound of any one of claims 1 -5 and 7-20, or a pharmaceutically acceptable salt thereof, wherein R7 is C 1-4 alkyl.
27. The compound of any one of claims 1-5 and 7-20, or a pharmaceutically acceptable salt thereof, wherein R7 is OR15.
28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein Ring A is C3-iocycloa!kyl.
29. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein Ring A is Ce-io aryl.
30. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl.
31. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein Ring A is 4 to 10-membered heterocycloaikyl,
32. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, adamantanyl, naphthyl, 1,2,3,4-tetrahydroquinoxalinyl, 3,4- dihydroqinazolinyl, 1,2,3,4-tetmhydroquinazolinyl, or pyridyl.
33. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein Ring A is 5 to 10-membered heteroaryl.
34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein at least one of RA, RB, Rc, and RD is other than hydrogen.
35. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein at least two of RA, RB, Rc, and RD are other than hydrogen.
36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein RA is Cy1,
37. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein RA is C6-io ryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1 , 2, 3, 4, or 5 substituents independently selected from RCy.
38. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein RA is 5-10 membered heteroaryl which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.
39. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein RA is pyrazolyl which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.
40. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein RA is 3 -methyl- lH-pyrazol-l-yl.
41. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein RA is C6-ioaryl optionally substituted by 1 , 2, 3, 4, or 5 substituents independently selected from RCy.
42. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein RA is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein RB is H,
44. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein RB is Cy2, halo, Ci-β alkyl, C2.6 alkenyl, C!-6 haloalkyl, CN} N02, ORa3, SR33, C(0)Rb3, C(0)NRc3Rd3, C(0)ORa3, 0C(O)Rb3, OC(0)NRc3Rd3, NRc3Rd3, NRc3C(0)Rb3, NRc3C(0)ORa3, NRc3C(0)NRc3Rd3 } NRc3S(0)Rb3 5 NRe S(0)2Rb3, NRc3S(0)2NRc3Rd3, S(0)Rb3, S(0)NRc3Rd3 } S(0)2Rfa3, or S(0)2NRe3Rd3, wherein said C|.6 alkyl and C2.6 alkenyl are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from Cy2, halo, Ci-6 alkyl, C2- 6 alkenyi, d-6 haioalkyl, CN, N02, ORa3, SRa3, C(0)Rb3, C(0)NRc3Rd3, C(0)ORa\ Ο^Ο^3, OC(0)NRc3Rd3, NRc3Rd3, NRc3C(0)Rb3 s NRc3C(0)ORa3, NRc3C(0)NRc3Rd3, NRc3S(0)Rb3, NRclS(0)2Rb3, NRc3S(0)2NRc3Rd3, S(0)Rb3 s S(0)NRc3Rd\ S(0)2Rb3, and S(0)2NRc3Rd3.
45. The compound of any one of claims 1 -42, or a pharmaceutically acceptable salt thereof, wherein RB is Cy2.
46. The compound of any one of claims 1 -42, or a pharmaceutically acceptable salt thereof, wherein RB is C6-io aryl or 5-10 membered heteroaiyl, each of which is optionally substituted by 1 , 2, 3, 4, or 5 substituents independently selected from RCy,
47. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein RB is halo, Ct.6 alkyl, C2.6 alkenyi, Ci-6 haioalkyl, CN, N02, ORa3, SR33, C(0)R 3, C(0)NRc Rd3, C(0)ORfl3, OC(0)Rb3 5 OC(0)NRc3Rd3, NRo3Rd3, NR 3C(0)Rb3, NRc3C(0)ORa3, NRc3C(0)NRc3Rd3, NRc3S(0)Rb3, NRc3S(0)2R 3, NRc3S(0)2NRc3Rd3, S(0)Rb 5 S(0)NR 3Rd3, S(0)2Rb3, or S(0)2NRc3Rd3, wherein said Ci-e alkyl and C2-6 alkenyi are each optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from Cy2, halo, Ci-6 alkyl, C2- 6 alkenyi, Ci.6 haioalkyl, CN, N02, ORa3, SRa3, C(0)Rb3, C(0)NRc3Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc3Rd3 s NRc3Rd3 } NRc3C(0)Rb3, NRc3C(0)ORa3, NRc3C(0)NRc3Rd3 ; NRc3S(0)Rb3, NRclS(0)2Rb3, NRc S(0)2NRc3Rd3 J S(0)Rb3 } S(0)NRc3Rd3, S(0)2Rb3, and S(0)2NRc3Rd3.
48. The compound of any one of claims 1 -42, or a pharmaceutically acceptable salt thereof, wherein RB is halo.
49. The compound of any one of claims 1 -48, or a pharmaceutically acceptable salt thereof, wherein Rc is H,
50. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt thereof, wherein Rc is halo, Ci.6 alkyl, C2.6 alkenyi, Ci-6 haioalkyl, CN, N02, ORa4, SRa4, C(0)Rb4, C(0)NRc Rd4, C(0)ORa4, OC(0)Rb4, OC(0)NRc4Rd4, NRc4Rd4, NRc4C(0)Rb4, R^CCC OR*4, NRc4C(0)NRc4Rd4, NRc S(0)Rb4, NRc4S(0)2RM, NRc S(0)2NRc4Rd4, S(0)RM, S(0)NRc4Rd4, S(0)2RM, or S(0)2NRc Rd4; wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Ce-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, Ci-6 alkyl, C2-6 alkenyl, Ci.6 haloalkyl, CN, N02) ORa4, SRa4, C(0)Rb4, C(0)NRc Rd4, C(0)ORa4, OC(0)RM, OC(0)NRc4Rd4, NRc Rd ) NRc4C(0)R 4, NRc4C(0)ORa4, NRc4C(0)NRc4Rd4, NRc4S(0)Rb4, NRc S(0)2Rb4, NRe4S(0)2NRc4Rd4, S(0)Rb ; S(0)NRc4Rd4, S(0)2Rb4, and S(0)2NRc4Rd4.
51. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt thereof, wherein R is H.
52. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt thereof, wherein RD is halo, Ci-β alkyl, C2-6 alkenyl, CM haloalkyl, CN, N02, ORa } SRa4 } C(0)Rb4, C(0)NRc4Rd4, C(0)ORa4, OC(0)Rb4, OC(0)NRc4Rd4 } NR^R*54, NRc C(0)Rb4, NRc4C(0)ORa4 J NRc4C(0)NRc Rd4, NRc4S(0)Rb4, NRc4S(0)2RM, NRe4S(0)2NRe4R 4 s S(0)Rb4, SCOJNR^R*1 , S(0)2Rb4, or S(0)2NRc4Rd4; wherein said Ci-6 alkyl and C2.6 alkenyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Ce-io aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, Ci-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, N02, ORa4, SRa4 ; C(0)RM, C(0)NRc4Rd4, C(0)ORa4, OC(0)Rb4, OC(0)NRc4Rd4 J NR^R*1 , NRc4C(0)Rb4, NRc C(0)ORa4, NRc C(0)NRc Rd4, NRc4S(0)Rb4, NRc S(0)2Rb4, NRc S(0)2NRc4Rd4, S(0)Rb4, S(0)NRc4Rd4, S(0)2Rb4 ; and S(0)2NRc4Rd4.
53 , The compound of any one of claims 1 -52, or a pharmaceutically acceptable salt thereof, having Formula Ila:
Figure imgf000399_0001
Ha.
54. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, having Formula li
Figure imgf000399_0002
55. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, having Formula lie:
Figure imgf000400_0001
lie.
56, The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, having Formula lid:
Figure imgf000400_0002
lid.
57. The compound of any one of claims 1 -52, or a pharmaceutically acceptable salt thereof, having Formula lie:
Figure imgf000401_0001
He.
58. The compound of any one of claims 53-57, or a pharmaceutically acceptable salt thereof, wherein L is 0.
59. The compound of any one of claims 53-57, or a pharmaceutically acceptable salt thereof, wherein L is NR4.
60. The compound of any one of claims 53-59, or a pharmaceutically acceptable salt thereof, wherein R3 is H.
61. The compound of any one of claims 53-60, or a pharmaceutically acceptable salt thereof, wherein R2 is CF3 and R3 is H.
62. The compound of any one of claims 53-61, or a pharmaceutically acceptable salt thereof, wherein R1 is H or Ci-io alkyl.
63. The compound of any one of claims 53-62, or a pharmaceutically acceptable salt thereof, wherein RA is 5-10 membered heteroaryl which is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.
64. The compound of any one of claims 53-62, or a pharmaceutically acceptable salt thereof, wherein RA is 5 to 6-membered heteroaryl optionally substituted by 1 , 2, or 3 substituents independently selected from RCy.
65. The compound of any one of claims 53-62, or a pharmaceutically acceptable salt thereof, wherein RA is Ce-io aryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.
66. The compound of any one of claims 53-62, or a pharmaceutically acceptable salt thereof, wherein RA is phenyl optionally substituted by 1 , 2, or 3 substituents independently selected from RCy.
67. The compound of any one of claims 53-66, or a pharmaceutically acceptable salt thereof, wherein RB is Cy2.
68. The compound of any one of claims 53-66, or a pharmaceutically acceptable salt thereof, wherein RB is H, halo, Ct-e alkyl, C2-6 alkenyl, Ci-β haloalkyl, CN, ORa\ C(0)NRc3Rd3, or C(0)ORa3, wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-6 haloalkyl, CN, N02j ORa3, SR33, C(0)RM, C(0)NRc3Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc3Rd3, NRc3Rd3 } NRc3C(0)Rb3, NRc3C(0)ORa3 5 NRc3C(0)NRc3R(f3, NR03S(O)Rb3, NRclS(O)2Rb , NRc3S(O)2NRc3Rd3 ; S(0)Rb3, S(0)NRc3Rd3, S(0)2Rb3, and S(0)2NRc3Rd3.
69. The compound of any one of claims 53-68, or a pharmaceutically acceptable salt thereof, wherein Rc is H.
70. The compound of any one of claims 53-69, or a pharmaceutically acceptable salt thereof, wherein RD is H,
71. The compound of any one of claims 53-70, or a pharmaceutically acceptable salt thereof, wherein R5 is H.
72. The compound of any one of claims 53-71 , or a pharmaceutically acceptable salt thereof, wherein R6 is H.
73. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, having Formula Ilia or Illb:
Figure imgf000403_0001
Illb.
74, The compound of claim 73, or a pharmaceutically acceptable salt thereof, wherein R2 is CF3.
75. The compound of any one of claims 73 and 74, or a pharmaceutically acceptable salt thereof, wherein R1 is H or Ci-io alkyi,
76. The compound of any one of claims 73-75, or a pharmaceutically acceptable salt thereof, wherein RA is 5-10 membered heteroaryl which is optionally substituted by 1 , 2, 3, 4, or 5 substituents independently selected from RCy.
77. The compound of any one of claims 73-75, or a pharmaceutically acceptable salt thereof, wherein RA is 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
78. The compound of any one of claims 73-75, or a pharmaceutically acceptable salt thereof, wherein RA is C6-io aryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.
79. The compound of any one of claims 73-75, or a pharmaceutically acceptable salt thereof, wherein RA is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
80. The compound of any one of claims 73-79, or a pharmaceutically acceptable salt thereof, wherein RB is Cy2,
81. The compound of any one of claims 73-79, or a pharmaceutically acceptable salt thereof, wherein RB is H, halo, Ci-e alkyl, C2.6 alkenyl, Ci-6 haloalkyl, CN, ORR\ C(0)NRc3Rd3, or C(0}ORa3, wherein said Ci.6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci-e haloalkyl, CN, N02, ORB\ SR83, C(0)Rb3, C(0)NRc3Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc3Rd\ NRc3Rd3, NRc3C(0)Rb3, NRc3C(0)ORa3, NRc3C(0)NRc3Rd3, NRc3S(0)Rb3, NRctS(0)2Rb3 ) NRc3S(0)2NRc3Rli3 J S(0)R 3, S(0)NRc3Rd3, S(0)2Rb3, and S(0)2NRc3Rd3.
82. The compound of any one of claims 73-81, or a pharmaceutically acceptable salt thereof, wherein Rc is H,
83. The compound of any one of claims 73-82, or a pharmaceutically acceptable salt thereof, wherein R is H,
84. A compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, having Formula IV:
Figure imgf000405_0001
IV.
85. The compound of claim 84, or a pharmaceutically acceptable salt thereof, wherein R2 is
CF3.
86. The compound of any one of claims 84 and 85, or a pharmaceutically acceptable salt thereof, wherein Rl is H or Ci-io alkyl,
87, The compound of any one of claims 84-86, or a pharmaceutically acceptable salt thereof, wherein RA is 5-10 membeied heteroaryl which is optionally substituted by 1 , 2, 3, 4, or 5 substituents independently selected from RCy.
88. The compound of any one of claims 84-86, or a pharmaceutically acceptable salt thereof, wherein RA is 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy,
89. The compound of any one of claims 84-86, or a pharmaceutically acceptable salt thereof, wherein RA is Ce-ioaryl optionally substituted by 1 , 2, 3, 4, or 5 substituents independently selected from
90. The compound of any one of claims 84-86, or a pharmaceutically acceptable salt thereof, wherein RA is phenyl optionally substituted by 1, 2, or 3 substituents independently selected from R^.
91. The compound of any one of claims 84-90, or a pharmaceutically acceptable salt thereof, wherein RB is Cy2.
92. The compound of any one of claims 84-90, or a pharmaceutically acceptable salt thereof, wherein RB is H, halo, CJ-6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, ORa3, C(0)NRo3Rd3, or C(O)0Ra3, wherein said Ci-6 alkyl and C2.6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci-e haloalkyl, CN, NC% OR"3, SR"3, C(0)Rb3, C(0)NRc3Rd3, C(0)ORfl3, OC(0)Rb3, OC(0)NRc3Rd3 ; NRc3Rd3, NRc3C(0)Rb3, NRc3C(0)ORa3 s NRc3C(O)NR03Rd3, NRc3S(0)Rb3, NRc,S(0)2Rb3, NRc3S(0)2NRc3Rd3 J S(0)Rb3, S(0)NRc3Rd3, S(0)2R 3, and S(0)2NRc3Rd3.
93. The compound of any one of claims 84-92, or a pharmaceutically acceptable salt thereof, wherein Rc is H.
94. The compound of any one of claims 84-93, or a pharmaceutically acceptable salt thereof, wherein RD is H.
95. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, having Formula Va:
Figure imgf000407_0001
96. The compound of claim 95, or a pharmaceutically acceptable salt thereof, wherein R2 is CF3.
97. The compound of claim 95 or 96, or a pharmaceutically acceptable salt thereof, wherein R1 is is H or Ci-io alkyl.
98. The compound of any one of claims 95-97, or a pharmaceutically acceptable salt thereof, wherein RA is 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from RCy.
99. The compound of any one of claims 95-97, or a pharmaceutically acceptable salt thereof, wherein RA is 5 to 6-membered heteroaryl optionally substituted by 1, 2, or 3 substituents independently selected from RCy.
100. The compound of any one of claims 95-97, or a pharmaceutically acceptable salt thereof, wherein RA is C6-io aiyl optionally substituted by 1, 2, or 3 substituents independently selected from RCy
101. The compound of any one of claims 95-97, or a pharmaceutically acceptable salt thereof, wherein RA is phenyl optionally substituted by 1 , 2, or 3 substituents independently selected from RCy.
102. The compound of any one of claims 95-101, or a pharmaceutically acceptable salt thereof, wherein RB is Cy2.
103. The compound of any one of claims 95-101, or a pharmaceutically acceptable salt thereof, wherein RB is H, halo, Ci-6 alkyl, C2-6 a!kenyl, Ci-e haloalkyl, CN, OR33, C(0)NRc3Rd3, or C(0)ORa3, wherein said Ci-6 alkyl and C2-6 aikenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci-6 haloalkyl, CN, NO2, ORa3, SR33, C(0)R 3, C(O)NR03Rd3, C(0)ORfl3, 0C(O)RM, OC(0)NRc3Rd 5 NRc3Rd3, NRc C(0)Rb3, NR^CfOJOR33, NRe3C(0)NRc3Rd3, NRc3S(0)Rb3, NRcIS(0)2Rb3, NRc3S(0)2NRc3Rd3, S(0)Rb3, S(0)NRc3Rd3, S(0)2Rb3, and S(0)2NRc3Rd3.
104. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, having Formula
Figure imgf000408_0001
105, The compound of claim 104, or a pharmaceutically acceptable salt thereof, wherein R2 is CF3.
106. The compound of claim 104 or 105, or a pharmaceutically acceptable salt thereof, wherein Rf is H or CMQ alkyl.
107. The compound of any one of claims 104-106, or a pharmaceutically acceptable salt thereof, wherein RB is Cy2.
108. The compound of any one of claims 104-106, or a pharmaceutically acceptable salt thereof, wherein RB is H, halo, Ct.6 alkyl, C2-6 alkenyl, Ci-6 haloalkyl, CN, ORa3, C(0)NRc3Rd3, or C(0)ORa3, wherein said Ci-6 alkyl and C -6 alkenyl are each optionally substituted with 1 , 2, or 3 substituents independently selected from halo, Ci-6 haloalkyl, CN, NC% OR33, SR33, C(0)Rb3, C(0)NRc3Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc3Rd3, NRc3Rdi, NRc3C(0)Rb3, NRc3C(0)ORa3, NRc3C(0)NRc3Rd3, NRc3S(0)Rb3, NRclS(0)2Rb3, NRc3S(0)2NRc3Rd3, S(0)Rb3, S(0)NRc3Rd3, S(0)2Rb3, and S(0)2NRc3Rd3.
109. The compound of any one of claims 104-108, or a pharmaceutically acceptable salt thereof, wherein Rc is H.
1 10. The compound of any one of claims 04-109, or a pharmaceutically acceptable salt thereof, wherein RD is H.
1 1 1. The compound of any one of claims 1 -52, or a pharmaceutically acceptable salt thereof, having Formula VII:
Figure imgf000410_0001
wherein a is 0, 1, 2, or 3.
112, The compound of claim 11 1, or a pharmaceutically acceptable salt thereof, wherein R2 is CF3.
1 13. The compound of claim 1 1 1 or 112, or a pharmaceutically acceptable salt thereof, wherein R1 is H or Ci-io alkyl.
114. The compound of any one of claims 111 - 113, or a pharmaceutically acceptable salt thereof, wherein RB is Cy2.
115. The compound of any one of claims 111 - 1 13 , or a pharmaceutically acceptable salt thereof, wherein RB is H, halo, C|.6 alkyl, C2.6 alkenyl, 0-6 haloalkyl, CN, ORa3, C(0)NRc3Rd3, or C(0)ORa3, wherein said Ci-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci-e haloalkyl, CN, N02, ORa3, SR83, C(0)Rb3, C(0)NRc3Rd3, C(0)ORa3, OC(0)Rb3, OC(0)NRc3Rd3, NRc Rd3, NRc3C(0)Rb3, NRc3C(0)ORa3, NRc3C(0)NRc3Rd3 5 NRc3S(0)Rb3, NRclS(0)2Rb3, NRc3S(0)2NRc3Rd3, S(0)Rb3, S(0)NRc3Rd3 } S(0)2Rb3, and S(0)2NRc3Rd3.
1 16. The compound of any one of claims 111-115, or a pharmaceutically acceptable salt thereof, wherein Rc is H.
1 17. The compound of any one of claims 111-116, or a pharmaceutically acceptable salt thereof, wherein RD is H.
118. The compound of any one of claims 1 1 1 -1 17, or a pharmaceutically acceptable salt thereof, wherein RCy is halo, Ci-6 alkyl, Ci-6 haloalkyl, 4-10 membered heterocycloalkyl, CN, N02) ORa5, SRa5, C(0)Rb5, C(0)NRcSRds, C(0)ORa5, NRc5RdS, S(0)2Rb5, and S(0)2NRc5Rds, wherein said Ci-6 alkyl and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, CN, N02> ORa5, SRa5, C(0)Rb5 5 C(0)NRc5Rd5, C(0)ORa5 5 OC(0)Rb5, OC(0)NRc5Rd5, NRc5Rd5, NRc5C(0)Rb5,
NRc5C(0)ORa5, NRc5 C (0)NRc5R<15 ; NRc5S(0)Rb5, NRcSS(0)2Rb5, NRc5S(0)2NRc5Rd5, S(0)RbS, S(0)NRcSRds, S(0)2R 5 5 and S(0)2NRc5Rd5.
1 9. The compound of any one of claims 1 - 118, or a pharmaceutically acceptable salt thereof, wherein the chiral carbon to which -C(0)OR! is attached has an S configuration.
120. The compound of any one of claims 1-110, or a pharmaceutically acceptable salt thereof, wherein the carbon to which -R2 is attached has an R configuration.
121. The compound of claim 1 selected from:
(3S)-8-(2-amino-6-((l R)-2,2,2-trifluoro- i -(3 -(3 -methyl- lH-pyrazol-1 ~yl)-4'- (methylsulfinyl)-[l, -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3- carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3-(3-methyI-lH-pyrazol-l-yl)-4'-(methylthio)- [1 ,l'-biphenyl]-4-yl) ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO [4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(3'-carboxy-3-(3-methyl- lH-pyrazol-l-yl)-[l;r-biphenyl]-4-yl)- 2,2}2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(3'-carboxy-3-(3-methyl-lH-pyrazol-l-yl)-[l ,l '-biphenyl]-4-yl)- 2,2,2-trifluoiOethoxy)pyrimidin-4-yi)-2,8-diazaspii [4,5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-l-(4,-cat^oxy-3-(3-methyl- lH-pyrazol-l-yl)-[lJl'-biphenyl]-4-yl)- 2,2,2-trifluoiOethoxy)pyrimidin-4-yl)-2J8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2J2-tnfluoi -l-(2-(3-methyl H-pyrazol-l-yl)
tetrahydi pyridin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-258-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-ammo-6-((R)-2,2,2-trifhioro~ 1 -(2-(3-methyl- 1 H-pyrazol- 1 -yl)-4-(pyridin-4- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2)2J2-trifluoi'o-l-(2-(3-iiiethyl-lH-pyrazol-l-yl)-4-(l-methyl-lH- pyrazol-4-yI)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspii'o[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2J2,2-trifluoiO-l-(4-(isoxazol-4-yl)-2-(3 -methyl- 1 H-pyrazol- 1- yi)phenyl)ethoxy)pynmtdin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-(3,6-dihydiO-2H-pyran-4-yl)-2-(3-methyl-lH-pyrazoi-l- yl)phenyl)-2)2,2-trifluoiOethoxy)pyrimidin-4-yl)-2>8-diazasphO[4.5]decane-3-carboxylic acid;
(S)-8-(6-((R)-l -(4-0 -acetyl-1 J2)3,6-ietrahydiOpyridin-4-yl)-2-(3-methyl- 1 H-pyrazol- 1- yl)phenyl)-2,2J2-trifluoroethoxy)-2-amiiiopyrimidin-4-yl)-2J8-diazaspii [4.5]decane-3- carboxylic acid;
(S)-8-(2-amino-6-((R)-2J2,2-trifluoiO-l-(4,-isopropoxy-3-(3-methyl-lH-pyrazol-l-yl)- [lj -bip enyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4,5]decaiie-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-^4'-dime^
yl)-2,2}2-trifluoiOethoxy)pyi'imidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2)232-trifliioiO-l-(4-(2-methoxypyridin-4-yl)-2-(3-methyl-lH- pyrazol-i-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8 2-amino-6-((R)-2,2!2-trifluoi -l-(4-(3-rneihyl-lH-indazol-6-yl)-2-(3-methyl-lH- pyi'azol-l-yl)phenyl)ethoxy)pynmidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)- 1 -(4*-(tert-butyl)-3-(3-meihyl- 1 H-pyrazol- 1 -yl)-[ 1 , 1 '-biphenyl]-4- yl)-2,2i2-trifluoi ethoxy)pyrimidin-4-yl)-2;8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4'-ethoxy-3-(3-methyl-lH-pyrazol-l-yl)-[l,r-bipheny!]-4-yl)- 2,2,2-trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-arnino-6-((R)-2)2)2-trifluoiO-l-(4-(2-methoxypyrimidin-5-yl)-2-(3-methyl-lH- pyrazol-l-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,252-trifluoro-l-(4-(6-methoxypyridin-3-yl)-2-(3-methyl-lH- pyrazol-l-yl)phenyl)ethoxy)pynmidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2 rifluoro- 1 -(3-(3-methyl- 1 H-pyrazol- 1 -yi)-[l ,1 '-biphenyl]-4- yl)ethoxy)pyi'imidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2}2,2-tiifluoro -(3-(3-methyl-lH-pyrazol-l-yl)-2',3, J4,,5'- tetrahydro-[l,r-biphenyl]-4-y])ethoxy)pyrimidin-4-yl)-2)8-diazaspiiO[4.5]decane-3-cai*boxyiic acid;
(S)-8-(2-amino-6-((R)-l-(3'-cyano-3-(3-methyl-lH-pyrazol-l-yl)-[l>r-biphenyl]-4-yl)- 2,2}2-trifluoiOethoxy)pyrimidin-4-yl)-2;8-diazaspiiO[4,5]decane-3-carboxylic acid;
(S)-8-(6-((R)-l-(4'-(acetamidomethyl)-3-(3-methyl-lH-pyrazol-l-yl)-[l ,l'-biphenyl]-4- yl)-2,2}2-ti fliioiOethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(6-((R)-l -(4'-(2-acetamidoethyl)-3-(3-methyl- 1 H-pyrazol-1 -yl)-[i , 1 '-biphenyl]-4- yl)-2J2,2-ti'ifliioi ethoxy)-2-aminopyrimidin-4-yl)-2)8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2)2,2-trifluoiO-l-(2-(3-methyl-lH-pyrazol-l -yl)-4-(quinolin-7- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(6-((R)-l -(4-(lH-indol-6-yl)-2-(3-metliyl-lH-pyrazol-l -yl)phenyl)-2,2,2- tri fluo roethoxy) -2-ami nopyrimidiii-4 -yl)-2, 8 -diazaspi ro [4.5] decane -3 - carboxyl ic acid;
(S)-8"(2-amino-6-((R)-l-(4'-(ammomethyl)-3-(3-methyl-lH-pyrazol-l -yl)-[ljr- biphenyl]-4-yl)-2;2,2-trifli;oiOethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluoiO-l-(3l-fluoiO-3-(3-methyl-iH-pyrazol- l-yl)-[lil'- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-ammo~6-((R)-2;2,2-tiifliioi - 1 -(2-(3-methyl-l H-pyrazol- 1 -yl)-4-(quinolin-6- yl)p enyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-252,2-trifluoi -l -(4'-methyl-3-(3-methyl-l H-pyrazol-1 -yl)-[l ,Γ- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-cai'boxylic acid;
(S)-8-(2-amino-6-((R)-l-^4'-dichl^^^^^
yl)-2;2,2-trifluoroethoxy)pyriniidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(3\4'-difluoro^^
yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2>8-diazaspiro[4.5]decane-3-carboxylic acid; (S)-8-(2-ammo-6-((R)-l-(4'-chloi -3-(3^
2,2,2 nfluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-tri¾oi -l -(2-(3-methyl-lH-pyrazol-l -yl)-4-(pyrimidin-5- yl)phenyI)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-cai'boxylic acid;
(S)"8-(2-amino-6-((R)-2,2,2-trifluoiO- 1 -(2-(3-methyl- 1 H-pyrazol- 1 -yl)-4-(piperidin-4- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiio[4,5]decane-3-carboxylic acid;
(S)-8-(2-ammo-6-((R)-2,2,2-trifluoiO- 1 -(2-(3-methyl- 1 H-pyrazol- 1 -yl)-4-(l - (methylsulfonyl)piperidin-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3- carboxylic acid;
(S)-8-(6-((R)-l-(4-(I-acetylpiperidin-4-yl)-2-(3-methyl-lH-pyrazol-l-yl)pheny!)-2,2,2- trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-ti'ifluoro-l-(2-(3-methyl-lH-pyrazol-l-yl)-4-(tetrahydi -2H- pyi-an-4-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2)2-trifliioi -l-(3'-methoxy-4'-(methoxycarbonyl)-3-(3--methyl- lH^yrazol-l -yl)-[l,r-biphenyl]-4-yl)ethoxy)pynmidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(3'-(ethoxycarbonyl)-3-(3-methyl-lH-pyi'azol-l -yl)-[l,l'- biphenyl] -yl)-2,2,2-ti'ifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)~l -(4'-(ethoxy
biplienyl]-4-yl)-2,2,2-trifIuoroethoxy)pyrn^^
acid;
(S)-8-(2-amino-6-((R)-l-(4-(3-carboxypiOpyl)-2-(3-methyl-lH-pyrazol-l -yl)plienyl)- 2,2J2-trifluoiOetlioxy)pyrimidin-4-yl)-2)8-diazaspii [4.5]decane-3-cai'boxylic acid;
(S)-8-(2-amino-6-((R)-l -(4-(2-carboxyethyI)-2-(3-methyl-m-pyrazol-l-yl)phenyl)-2,2}2- ti'ifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l -(4-(3-ethoxy-3-oxopropyl)-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoiOethoxy)pyi4midin-4-yl)-2,8-diazaspiiO[4,5]decane-3-carboxylic acid;
8-(2-amino-6-((R)-2,2,2-trifluoro- l-(2-(3-methyl- 1 H-pyrazol- 1 - yl)phenyl)ethoxy)pyrimidin-4-yl)-2J8-diazaspitO[4.5]decane-3-carboxylic acid; 8-(2-amino-6-((R)- 1 -(4-chloro-2-(3-methyl- 1 H-pyrazol- 1 -yl)phenyl)-2,2,2- trifluoroethoxy)pyiimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(R)-8-(2-amino~6"((R)-l-(4-chloi -2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2}2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-chloi -2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoiOethoxy)pynmidin-4-yl)-2,8-diazaspiro[4.5]decaiie-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-252,2-trifluoiO-l-(2-(3-methyl- lH-pyrazol-l - yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)- 1 -(3-chloro-2-(3-methyl- 1 H-pyrazol- 1 -yl)phenyl)-2,2,2- trifluoroethoxy)pynmidin-4-yl)-2J8-diazaspiro[4.5]decane-3-cai'boxylic acid;
(S)-8-(2-amino-6-((R)-2)2>2-trifluoiO- 1 -(2-(3-methyl- 1 H-pyrazol- 1 -yl)-4- (trifluoi methyl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid
(S)-8-(2-amino-6-((R)-2,2,2-trifluoiO-l-(4-methyl-2-(3-methyl-lH-pyrazol-i- yl)phenyl)ethoxy)pyrimidin-4-yl)-2;8-diazaspiro[4.5]decane-3-carboxylic acid;
8-(2-amino-6-((R)-2,2,2-tnfliioiO-l-(4-fluoi -2-(3 -methyl- 1 H-pyrazol- 1 - yl)phenyl)ethoxy)pynmidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
8-(2-ammo-6-((R)~2,2,2-trifluoi - 1 -(4-methoxy-2-(3 -methyl- 1 H-pyrazol- 1 - yl)phenyl)ethoxy)pyrimidin-4-yl)-2J8-diazaspiiO[4.5]decane-3-carboxylic acid;
8-(2-amino-6-((R)-l-(5-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoiOetlioxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluoi -l-(4-methoxy-2-(3-methyl-lH-pyrazol-l- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxyiic acid;
(S)-8-(2-amino-6-((R)-l-(4-bromo-2-(3-methyl-l H-pyrazol- 1 -yl)phenyl)-2,2s2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxyHc acid;
(S)-8-(2-amino-6-((R)-l-(5-biOmo-2-(3-niethyl-lH-pyrazol-l -yl)phenyl)-2,2,2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-232J2-trifluoi -l-(6-methyl-2-(3-methyl-lH-pyrazol-l-yl)pyridin- 3-yl)ethoxy)pyrimidin-4-yl)-2)8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-ethyl-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifiuoro- 1 ~(2-(3-methyl~ 1 H-pyrazol- 1 -y l)-4- piOpylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-cai-boxyHc acid;
(S)-8-(2-amino-6-((R)-l-(4-butyl-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2J2- ti'ifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(3S)-8-(2-amino-6-((lR)- l-(4-(l,2-dihydi xyethyl)-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifliioiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-ammo-6-((R)-l-(4-cyano-2-(3-methyl-lH-pyiazol-l-yl)phenyl)-2,2)2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-carbamoyl-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- ti'ifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)- 1 -(4-carboxy-2-(3-methyl- 1 H-pyrazol- 1 -yl)phenyl)-2,2,2- trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-(ethoxycarbonyl)-2-(3-methyl-lH-pyrazol-l-yl)phenyl)- 2J2,2-trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiio[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-ti fiuoi -l-(4-(((l ,l)l)3,3)3-hexafluoi -2-methylpi pan-2- yl)oxy)cai'bonyI)-2-(3-methyl-lH-pyrazol-l-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro [4.5]decane-3 -carboxyiic acid;
(S)-8-(2-amino-6-((R)-2)2,2-trifluoi -l-(2-(3-methyl-lH-pyrazol-l-yl)-4- (pi poxycarbonyl)phenyl)ethoxy)pyrimidin-4-yl)-2j8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R> 1 -(4-(butoxycarbonyl)-2-(3-methyl- 1 H-pyrazol-1 -yl)phenyl)- 252,2-trifliioiOethoxy)pyrimidin-4-y!)-2,8-diazaspiro[4,5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-(tert-birtoxycarbonyl)-2-(3-methyl-lH-pyrazol-l-yl)phenyl)- 2i2)2-irifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2)2,2-trifluoro-l -(4-(isobutoxycarbonyl)-2-(3-methyl-lH-pyrazoI- l-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)- 1 -(4-((cyclopentyloxy)carbonyl)-2-(3-methyl~l H-pyrazol- 1 - yl)phei yl)-2>2,2-trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-cat,boxylic acid;
(S)-8-(2-amino-6-((R)-2,252-trifluoi -l-(2-(3-methyl-lH-pyrazol-l-yl)-5- vinylphenyl)ethoxy)pyrimidin-4-yl)-2J8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2)2,2-trifliioro-l-(2-(3-methyl-lH-pyrazol-l-yl)-5-((E)-prop-l-en- l-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-l-(5-((E)-but-l-en-l-yl)-2-(3-methyi-lH-pyrazol-l-yl)phenyl)- 2)2,2-ti'ifluoroetlioxy)pyrimidin-4-yl)-2J8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)- 1 -(5-((E)-2-carboxy vinyl)-2-(3 -methyl- lH-pyrazol- 1 -yi)phenyl)- 2,2)2-trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(3'J4'-dimethyi-4-(3-methyl-lH-pyrazol-l-yl)-[l ,l'-biphenyl 3- yl)-2,2,2-trifluoroethoxy)pynmidin-4~yl)-2,8-diazaspiiO[4,5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(3'-carboxy-4-(3-methyl-lH-pyrazol-l -yl)-[l ,l'-biphenyl]-3-yl)- 2,252-trifluoi eihoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4'-carboxy-4-(3-methyl-lH-pyrazol-l-yl)-[l,l'-biphenyl]-3-yl)- 252,2-trifluoroethoxy)pyrimidin-4-yl)-2J8-diazaspiro[4,5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(3'-((E)-2-carboxyvinyl)-4-(3-methyl-lH-pyrazol-l-yl)-[l,l'- biphenyl]-3-yl)-2,2,2-trifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4'-((E)-2-caAoxyvinyl)-4-(3-methyl-lH-pyrazol- l-yl)-[l ;l'- biplienyl]-3-yl)-2,2,2-trifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4,5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(3'-(2-carboxyethyl)-4-(3-methyl-lH-pyrazol-l-yl)-[l,r- biphenyl]-3-yl)-2,2J2-trifluoiOethoxy)pyrimidin-4-yl)-258-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)- l-(4'-(2-carboxyethyl)-4-(3-methyl- 1 H-pyrazol- 1 -yl)-[l ,r- biphenyl]-3-yi)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2)8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2;2,2-tii¾oi -l-(4'-(hydiOxymethyl)-3'-methyl-4-(3-metbyl-lH pyrazol-l-yl)-[l, -biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2}2-trifiuoi -l-(3'-(hydiOxymethyl)-4'-methyl-4-(3-methyl-lH- pyrazol-l-yl)-[l, -biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxyiic acid;
(S)-8-(2-amino-6-((R)-2i2,2-tnfluorO"l -(4-(3-methyl-lH-pyrazol-l-yl)-[l,l'^^ yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid; (Si-S^-amino-e-CC^-l-CS'^'-difluoiO^-CS-methyl-lH- yrazol-l-y -t l'-bi heny^-S- yl)-2,2,2-ti,ifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carbo ylic acid;
(S)-8-(2-amino-6 (R)-l -(3^4'-dichloi^^
yl)-2)2,2-trifluoiOethoxy)pyiimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4'-chloro-4-(3-methyl-lH-pyrazol-l-yl)-[l5l '-biphenyl]-3-yi)- 2,232-trifluoi ethoxy)pyrimidin-4-yI)-2,8-diazaspit [4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(2'-(ethoxycarbonyl)-4-(3-methyl-lH-pyrazol-l-yl)-[l,l '- biphenyl]-3-yl)-2,2J2 iifluoiOethoxy)pyrimidin"4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l -(4'-(ethoxycarbonyl)-4-(3-methyl-lH-pyrazol-l-yl)-[l,l'- biphenyl]-3-yl)-2,2,2 rifluoi ethoxy)pyrimidin-4-yl)~2,8-diazaspiro[4,5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-ethyl-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2}2- ti,ifluoiOethoxy)pyi,imidm-4-yl)-2,8-diazaspiro[4.5]decane-3-caiboxylic acid;
S)-8-(2-amino-6-((R)-2)2!2-trifluoiO-l-(2-(3-methyl-lH-pyrazol-l-yl)-5- pi'opylphenyi)ethoxy)pyrimidin-4-yl)-2,8-diazasphO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-butyi-2-(3-met yl-lH-pyrazol-l -yl)phenyl)-2,2}2- tnfluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-Amino-6-((R)- 1 -(5-(ethoxycarbonyl)-2-(3-methyl- lH-pyrazol- 1 -yl)phenyl)- 2,2,2-trifluoro ethoxy)pyrimidin-4-yl)-2!8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-Amino-6-((R)-l -(5-carboxy-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-232,2- trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-Amiiio-6-((R)-2,2,2-trifluoiO-l -(4-(hydroxymethyl)-2-(3-methyl- lH-pyrazol-1 - y l)phenyl) ethox ) pyrimidin-4 -y 1) -2 , 8 -diazaspiro [4.5 ]decane -3 -carboxy lie acid;
(S)-8-(2-amino-6-((R)-l-(4-((dimethylamino)methyl)-2-(3-methyl-lH-pyrazol-l- yl)plienyl)-2}2,2-trifluoi ethoxy)pyrimidin-4-yl)-2>8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(6-((R)-l -(4-Bromo-2-(3-methyl-l H-pyrazol-1 -yl)phenyl)-232)2-trifluoiOethoxy)-2- methylpyrimidin-4-yl)-2>8-diazaspiiO[4.5]decane-3-carboxylic acid ;
(S)-8-(6-((R)-l -(4-chloiO-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoiOeihoxy)-2- methyl pytimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid; (S)-8-(2-methyl-6-((R)-2,252-trifluoro-l-(4-(2-methoxypyridin-4-yl)-2-(3-methyl-lH- pyrazol-l-yl)p enyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-methyl-6-((R)-2s2J2-tΓifiuolΌ-l-(3-(3-methyl-lH-pyrazol-l-yl)-4,- (methylsulfonyl)-[l, -biphenyl]-4-yl)ethoxy)pyi midin-4-yl)-2,8-diazaspiiO[4.5]decane-3- carboxylic acid;
(S)-8 6-((R)-H3\4'-difluoro-3-(3-me
trifluoroethoxy)-2-methylpynmidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(6-((R) -^4 imetbyl-3-(3-me ^
tt'ifluoiOethoxy)-2-methylpyrimidin-4-yl)-258-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(6-((R)-l-(3'-(ethoxycarbonyl)-3-(3-methyl-lH-pyrazoi-l-yl)-[l5r-biphenyl]-4-yl)- 2J2,2-triiluoiOethoxy)-2-methylpyrimidin-4-yl)-2;8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-methyl-6-((R)-2,252-trifliioro-l-(4-(6-methoxypyridin-3-yl)-2-(3-methyl-lH- pyrazol-l-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8--diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-metliyl-6-((R)-2J2,2-tii¾oro-l-(4-(2-methoxypyrimidin-5-yl)-2-(3-methyl-lH- pyrazol-l-yl)phenyl)ethoxy)pyrimidin-4-yi)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(6-((R)~ 1 -(2\4'-dimethoxy-3-(3-methyl- 1 H-pyrazol- 1 -yl)-[l , 1 '-biphenylj-4-yl)- 2;2s2-trifluoiOethoxy)-2-methylpynniidin-4-yl)-2,8-diazaspii [4,5]decane-3-carboxylic acid;
(S)-8-(6-((R)-l -(4'-(etlioxycarbonyl)-3-(3-methyl-lH-pyrazol-l-yl)-[l 5 l'-biphenyl]-4-yl)- 2,2)2-trifluoroeihoxy)-2-methylpynmidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(6-((R l-(4,-(dimethylcavbamoyI)-3-(3-meihyl-lH-pyrazoi- 1 -yl)-[l , 1 '-biphenylj-4- yl)-2,2,2-tiifluoroethoxy)-2-methylpyiimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-methyl-6-((R)-2,2i2-ti'ifluoro-l-(4-(2-meihoxypyridin-3-yl)-2-(3-methyl-lH- pyi'azol-l-yl)phenyl)et oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-methyl-6-((R)-2,2)2-tfiiluoiO-l-(3'-fluoro-4'-methoxy-3-(3-methyl-lH-pyrazol- l-yl)-[l,r-biphenyl]-4-yl)ethoxy)pyrimidin-4-yI)-2,8-diazaspitO[4,5]decane-3-carboxylic acid;
(S)-8-(6-((R)-l -(3'-(dimethylcarbamoyl)-3-(3-methyl-lH-pyrazol-l-yl)-[lJl'-biphenyl]-4- yl)-2J2,2-trif uoiOe†hoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-methyl-6-((R)-2,2J2 lύfluoro-l-(2^4 6'-trimetll l-3-(3-meth l-lH- razol-l-yl)- [l, -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-methyl-6-((R)-2;2,2-trifluoiO-l -(4,-isopiOpoxy-3-(3-methyl-lH-pyrazol-l-yl)- [l, -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid; (S)-8-(2-methyl-6-((R)-2,2,2-trifluoro- 1 -(2'-methoxy-3 -(3 -methyl- lH-pyrazol- 1 -yl)-[l , 1'- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4,5]decane-3-carboxylic acid;
(S)-8-(2-methyl-6-((R)-2,2,2-trifluoiO-l -(3'-methoxy-4,-(metlioxycarbonyl)-3-(3-methyl- lH-pyrazol-l-yl)-[l, -biplienyl]-4-yi)ethoxy)pyrimidin-4-yl)-258-diazaspiro[4.5]decane-3- carboxylic acid;
(S)-8-(6-((R)-l-(4'-(tert-butyl)-3-(3-methyl-lH-pyrazol-l-yl)-[l)r-biphenyl]-4-yl)-252,2- trifluoi'oethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspii'o[4.5]decane-3-cai'boxylic acid;
(S)-8-(6-((R> 1 -(4'-ethoxy-3-(3-methyl- lH-pyrazol-1 -yl)-[l , 1 '-biphenyl]-4-yl)-2,2,2- trifluoiOethoxy)-2-methylpyrimidjn-4-yl)-2,8-diazaspiiO[4.5]decane-3-cavboxylic acid;
(S)-8-(2^nethyl-6-((R)-2,2,2-trifluoro- 1 -(3-(3-methyl- 1 H-pyrazol- 1 -yl)-4'- (trifluoromethoxy)-[lj -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4,5]decane-3- carboxylic acid;
(S)-8-(2-methyl-6-((R)-2,2,2-trifluoiO-l-(3'-(methoxycarbonyl)-3-(3-methyl-lH-pyrazol- l-yl)-[l, -biphenyl]-4-yl)ethoxy)pyiimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-methyl-6-((R)-2,2,2-trifluoiO-l -(2-(3-methyl-lH-pyrazol-l -yl)-4-(pyrimidin-5- yl)phenyl)ethoxy)pynmidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-methyl-6-((R)-2)2,2-trifluoi -l-(3'-methoxy-3-(3-methyl-lH-pyrazol-l-yl)-[l,r- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2)8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-methy]-6-((R)-2)252-trifluoiO-l-(3'-isopi pyl-3-(3-methyl-lH-pyrazol-l -yl)- [l ,l'-biplienyl]-4-yl)ethoxy)pyrimidiii-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-methyl-6-((R)-2,2,2-trifluoiO- 1 -(S'-fliioro-S-CS-methyl-lH-pyrazol-l -yl)-[l ,Γ- bipheny3]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-methyl-6-((R)-2,2}2-trifluoi -l-(2-(3-methyl-lH-pyrazol-l-yl)-4-(pyridin-3- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-methyl-6-((R)-2}2,2-tniluoiO-l-(3'-methoxy-3-(3-methyl-lH-pym
biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2J8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-methyl-6-((R)-2,2,2-trifluoro-l -(2-(3-methyl-l H-pyrazol-1 -yl)-4-(pyridin-4- yl)phenyl)ethoxy)pynmidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
8-(6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2J2,2-trifluoiOethoxy)-2- phenoxypyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid; 8-(6-((R)-l-(4-chloro-2-(3-methyl- lH-pyraz0l-l-yl)phenyl)-252J2-trifluoi ethoxy)-2- (cyclohexyloxy)pyiimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
8-(6-((R)-l-(4-chloiO-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-252,2"trifluoiOethoxy)-2- (cyclohexylamino)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(6 (R)-l-(4-chloi -2-(3-methyl-lH-pyrazol-l-yi)phenyl)-2)2,2-trifliioiOethoxy)-2- (cyclob tanecarboxamido)pyrimidin-4-yl)-2J8-diazaspii [4.5]decane-3-cai'boxylic acid;
(S)-8-(2-amino-6-((R)-l -(4-chloi -2-(2-oxopyi Olidin-l-yl)phenyl)-2,2,2-trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)- 1 -(3',5-dichloro-[l , 1 '-biphenyl] -2-yl) -2,2,2- trifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloiO-3,-methyl-[l,r-biphenyl]-2-yl)-2,2,2- tiinuoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-cai'boxylic acid;
8-(2-amino-6-((R)- 1 -(5-chloro-[l , 1 ,-biphenyl]-2-yl)-2,2J2-trifluoiOethoxy)pyrimidm-4- yl)-2,8-diazaspiiO[4,5]decane-3-carboxylic acid;
8-(2-amino-6-((R)-l-(2'-amino-5-chloro-[l}r-biphenyl]-2-yl)-2,2)2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4,5]decane-3-carboxylic acid;
8-(2-amino-6-((R)-l-(5-chloro-3l-niti -[l,l,-biphenyl]-2-yl)-2;2,2- tnfluoroethoxy)pyrimidin-4-yl)-2J8-diazaspiro[4.5]decane-3-cai,boxyiic acid;
8-(2-amino-6-((R)-l-(3'-amino-5-chloiO-[l;l ,-biphenyl]-2-yl)-2)2J2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxyiic acid;
8-(2-amino-6-((R)-l -(5-chloiO-4'-nitro-[ 1 , 1 '-biphenyl]-2-yl)-2,2,2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
8-(2-amino-6-((R)-l-(4,-amino-5-chloiO-[l>l!-biphenyl]-2-yl)-2J2;2- trifliioi ethoxy)pyi'imidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-chloi -2-(6-methylpyridin-2-yl)phenyl)-252s2- trifluoroethoxy)pyrimidiii-4-yl)-2,8-diazaspiiO[4,5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloi -3'-(ethylsulfonyl)-[l,l'-biphenyl]-2-yl)-2,2}2- tiifluoiOethoxy)pyi midin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloiO-3'-(pi pylsulfonyl)-[l,l'-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyiimidin-4-yl)-2J8-diazaspiro[4.5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)- 1 -(3'-(butylsulfonyl)-5-chloro-[l , 1 '-biphenyl]-2-yI)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2;8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloiO-3'-(liydiOxymetbyl)-[l5r-biphenyl]-2-yl)-2)2)2- ti*ifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-aminO"6-((R)-l-(5-chloro-3,-(meihylsulfonamido)-[l5r-biphenyl]-2-yl)-2,252- trifluoi ethoxy)pyrimidin-4-yl)-2)8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloiO-3'-(2-oxopyrrolidin-l-yl)-[l,r-biphenyl]-2-yl)-2,2,2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloi -3'-(3-methyl-2-oxoimidazolidin-l-yl)-[l}l,-biphenyl]- 2-yl)-2J2,2-trifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)- 1 -(5-chloro-3'-(trifluoiOmethyl)-[l , 1 '-biphenyl]-2-yl)-2,2,2- trifluoiOethoxy)pynmidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloiO-[l,l'-biphenyl]-2-yl)-2)252-trifluoroetlioxy)pyiimidiii- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-chloi -2-(5-chloiOthiophen-2-yl)phenyl)-2,2J2- trifluoiOethoxy)pyi,imidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-chloro-2-(l-methyl-lH-pyrazol-3-yl)phenyl)-2t2,2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspii'o[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloiO-3*-sulfamoyl-[l5l,-biphenyl]-2-yl)-2J2)2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspitO[4,5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloro-3,-hydiOxy-[l,r-bipheny]]-2-yl)-2J2,2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S 8-(2-amino-6-((R)-l -(5-chloro-3'-(methylsulfonyl)-[l , 1 '-biphenyl]-2-yl)-2,2,2- trifluoi ethoxy)pyrin"iidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)- 1 -(5-chloro-3'-cyano-[ 1 , 1 '-biphenyl]-2-yl)-2,252- trifluoiOethoxy)pyiimidin-4-yl)-2}8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloiO-3'-methoxy-[l)r-biphenyl]-2-yl)-2,2J2- trifluoroethoxy)pyrimidin-4-yI)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(3'-(aminomethyi)-5-chloiO-[l 5l'-biphenyl]-2-yl)-252,2- trifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid; (S)-8-(6-((R> 1 -(3'-(aciylamidomethyl)-5-chloro-[l ,1 '-biphenyl]-2-yl)-2,2,2- ti'ifluoroethoxy)-2-aminopyrimidin-4-yl)-2}8-diazaspiiO[4,5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(3,-carboxy-5-chloro-[l '-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(3'-carbamoyl-5-chloro-[lir-biphenyl]-2-yl)-2,2;2- trifluoroethoxy)pyi,imidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino~6-((R)- 1 -(5-chloro-4'-(methylsulfonyl)-[ 1 , 1 '-biphenyl]-2-yl)-2,2,2- trifluoi'oethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)- 1 - (5-chloro-4'-sulfamoy , 1 '-biphenyl]-2-yl)-2,2,2- trifliToroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)- 1 -(4'55-dichloiO-3'-iluoiO-[ 1 , 1 '-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloiO-3,-isopiOpoxy-[ltl'-biphenyl]-2-yl)-2,2,2- ti'ifluoiOethoxy)pyiimidin-4-yl)-2)8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloiO-3'-ethoxy-[l,l '-biphenyl]-2-yl)-252J2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(3'J5-dichioiO-4'-ethoxy-[l;l,-biphenyl]-2-yl)-2,2,2- tnfluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(3\5-dichloro-4'-methyl-[l3l'-biphenyl]-2-yl)-2!2)2-- trifluoi ethoxy)pynmidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxyHc acid;
(S)-8 2-amino-6-((R)-i-(3^5-dichioiO-4'-isoprapoxy-[l,l '-biphenyl]-2-yl)-2J2}2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspira[4.5]decane-3-cai,boxylic acid;
(S)-8-(2-amino-6-((R)-l -(5-chloro-3'-fluoiO-4,-isopropoxy-[l,l,-biphenyl]-2-yl)-2,2J2- trifluoi ethoxy)pyrimidin-4-yl)-2)8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4'55-dichloro-3'-(trifluoiOmethyl)-[lJl,-biphenyl]-2-yl)-2>2)2- trifluoi'oethoxy)pyi,imidin-4-yl)-2I8-diazaspii'o[4.5]decane-3-cai'boxyiic acid;
(S)-8-(2-amino-6-((R)-l-(3',5-dichloiO-5'-fluoiO-[l5l'-biphenyl]-2-yl)-2,2J2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(3'-(tert-butyl)-5-chloi -[l,l'-biphenyl]-2-yl)-2}2,2- tnfluoroethoxy)pyrimidin-4-yl)-2J8-diazaspiro[4.5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-l-(3 5-dichlolΌ-5·-(tl■ifluolΌmethyl)-[l;l,-bi henyl]-2-yl)-2,2,2- trifluoi ethoxy)pyi'imidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloro-3'-fluoiO-5,-(trifluoiOmethyl)-[l)r-biphenyl]-2-yl)- 2,2J2-trifluoi ethoxy)pyi,imidin-4-yl)-2,8-diazaspiro[4.5]decane-3-cavboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloiO-3'-methoxy-[l,l,-biphenyl]-2-yl)-2)2,2- ti'ifluoroethoxy)pyrimidin-4-yl)-258-diazaspii [4.5]decane-3~carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloiO-3'-fluoi -[l,lf-biphenyl]-2-yl)-2i2,2- trifluoroethoxy)pynmidm-4-yl)-2,8-diazaspiiO[4.5]decane-3-cai,boxyHc acid;
(S)-8-(2-amino-6-((R)-l-(4';5-dichloi -3'-methyl-[l,l,-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pynmidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l -(5-chloiO-3'i5'-difluoiO-[ljr-biphenyl]-2-yl)-2,2,2- trifluoi'oethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S 8-(2-amino-6-((R)-l-(3'}5-dichloro-4'-fluoro-[l,l'-biphenyl]-2-yl)--2,2J2- trifluoiOethoxy)pyt'imidin-4-yl)-2,8-diazaspiio[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)- 1 -(5-chloiO-3, J4'-difluoio-[l , l'-biphenylj^-yl)-^^- trifliioiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxyiic acid;
(S)-8-(2-amino-6-((R)- 1 -^5-dichloro^
tiifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloiO-3'-(ethoxycarbonyl)-[l5l"-biplienyl]-2-yl)-2}2,2- trifluoiOethoxy)pyrimidin-4-yl)-2}8-diazaspiro[4.5]decane-3-cai-boxyIic acid;
(S)-8-(2-amino-6-((R)-l-(4-chloi -2-(2-methoxyethoxy)phenyl)-2,2,2- trifluoioethoxy)pyiimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(3S)-8-(6-(l-((lr,3r,5S}7S)-adamantan-2-yl)ethoxy)-2-aminopyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-caiboxylic acid;
(S)-8-(6-((lr,3r,5S,7S)-adamantan-2-ylmethoxy)-2-aminopyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid;
8-(4-amino-6-((naphtbalen-2-ylmethyl)amino)-l,3,5-triazin-2-yl)-2J8- d i azaspiro [4.5]decane -3 -carboxylic acid;
8-(4-(([I,r-biphenyl]-4-yImethyl)amino)-6-amino-l,3,5-triaz;in-2-yl)-2>8- di azaspiro [4 , 5] decane- 3 -carboxylic acid ; 8-(4-amino-6-((2-(piperidin-l-yl)benzyl)amino)-l,3,5-ti,iazin-2-yi)-2,8- diazaspiro[4.5]decane-3-caiboxylic acid;
8-(4-(([l,l'-biphenyl]-3-ylmethyl)amino)-6-amino-l,3j5-tnazin-2-yl)-2)8- diazaspi ro [4.5]decane-3 -carboxylic acid;
8-(4-amino-6-(((R)-l-(naphthalen-2-yl)ethyl)amino)-l,355-triazin-2-yl)-258- diazaspiro[4.5]decane-3-carboxylic acid;
8-(4-amino-6-((R)-l-(4-chIoi -2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2}2,2- tnfluoi'oethoxy)-l,3,5-tnazin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((2-(piperidin-l-yl)benzyl)amino)pyrimidin-4-yl)-2,8- diazaspiro[4,5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((2-phenoxy-6-(piperidin-l-yl)benzyl)amino)pyrimidin-4-yl)-2,8- d iazaspiro [4.5 ] de cane-3 - carboxylic acid ;
(3S)-8-(6-(((3S,5S)-adamantan-l-ylmethyl)amino)-2-aminopyrimidin-4-yl)-2,8- diazaspiiO[4.5]decane-3-carboxylic acid;
3S)-8-(6-((i-((lR,3S,5S)-adamantan-l-yl)ethyl)amino)-2-aminopyrimidin-4-yl)-2,8- diazaspiro [4 , 5]decane-3 -carboxylic acid;
(S)-8-(2-amino-6-((R)-l -(3'-chlora-[l ,11-biphenyl]-2-yI)-2,2)2-trifluoi ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4,5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro- l-(3'-fluoro-[l,l'-bip enyl]-2-yl)ethoxy)pynmidi 4-yl)-2,8-diazaspiiO[4.5]decane-3-cai'boxylic acid;
(S)-8-(5-((R)- 1 -(4-chloro-2-(3-methyl-lH-pyrazol-l -yl)phenyl)-2,2,2- tnfluoiOethoxy)pyndazin-3-yl)-2,8-diazaspii'o[4.5]decane-3-carboxyHc acid;
(S)-8-(4-((R)-2,2,2-trifluoiO-l-(2-(3-methyl-lH-pyrazol-l-yl)phenyl)ethoxy)pyridin-2- yl) -2 , 8 -diaz spiro [4.5 ] decane-3 -carb oxylic acid ;
(S)-8-(4-((R)-l -(4-chloiO-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2}2)2- trifluoiOethoxy)pyridin-2-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(4-((R)-l-(4-Chloro-2-(3-methyl-lH-pyrazol-l-yl)plienyl)-2J2,2-trifluoiOethoxy)-6- phenoxypyrimidin-2-yl)-2t8-diazaspiro[4.5]decane-3-carboxylic acid;
(3S)-8-(2-Amino-6-(l -(2,6-dibromophenyi)-2)2J2-trifluoiOethoxy)pyrimidin-4-yl)-2,8-- diazaspi ro [4.5 Jdecane -3 -carboxy 1 ic acid ; (S)-8-(2-Amino-6-((R)-l-(2J5-dibiOmophenyl)-2,2>2-trifluoiOethoxy)pynmidin-4-yl)-2)8- diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-Amino-6-((R)-2)2,2-trifliioi -l-(3,-(methylsulfonyl)-4-piOpyl-[l,l,-biphenyl]-2- yl)ethoxy) pyi,imidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-Amino-6-((R)-2,2)2-triiluoi -l-(3,-(methylsulfonyl)-4-((E)-piOp-l-en-l-yl)- [1 ,1 '-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspii'o[4,5]decane-3-carboxylic acid;
(S)-8-(6-((R)-l-([l51^4 l',-terphenyl]-2'-yl)-252,2-tiifluoi ethoxy)-2-aminopyrimidin-4- yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(6-((R)-l-([l )1^3 1"-terphen l]-2,-yl)-2,2,2-trifluOlΌethoxy)-2-ammopyrimidin-4- yi)-2,8-diazaspiiO[4.5]decane-3-carboxyiic acid;
(S)-8-(2-amino-6-((R)-l -(3;4-dimethyl-3"-(methylsulfonyI)-[l ,Γ^',Ι ,'-terphenyl]-4,-yl)- 2J2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxyiic acid;
(S)-8-(2-amino-6-((R)-2}2,2-trifluoro-l-(3'-(meihylsulfonyl)-5-(quinolin-6-yl)-[l,l'- biphenyl]-2-yl)ethoxy)pyi'imidin-4-yl)-2,8-diazasphO[4.5]decane-3-carboxylic acid;
(S)~8 2-amino-6-((R)-2)252-trifluoiO-l-(3,-(methylsulfonyl)-5-((E)
biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspitO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2J2i2-trifluoro- 1 -(3'-(methylsulfonyl)-5-propyl-[l , 1 '-biphenyl]-2- yl)ethoxy)pyrimidin-4-yl)-2,8-diazasphO[4.5]decane-3-carboxylic acid;
(S)-8-(6-((R)-l -([lJl,-biphenyl]-4"yl)-2,2J2-tnfluoroethoxy)-2-aniinopyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxy]ic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluoiO-l-(4-(l-methyl-lH-indazol-5- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2J2,2-trifluoi -l-(4-(l-metliyl-lH-benzo[d]imidazoi-5- yi)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(6-((R)-l -(4-(lH-benzo[d]imidazol-5-yl)phenyl)-2,2,2-irifluoiOethoxy)-2- aminopyrimidin-4-yl)~2t8-diazasphO[4.5]decane-3-carboxyiic acid;
(S)-8-(2-amino-6-((R)-2,2)2-trifluoiO-l-(3,-fluoro-4'-methoxy-[l,l,-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2}8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-(benzo[d]isothiazol-6-yl)phenyl)-252J2- tnfluoiOethoxy)pyi'imidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-l-(4-(benzo[d]isoxazol-6-yl)phenyl)-2,2;2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(6-((R)-l-(4 lH-indazol-6-yl)phenyl)-2)2)2-tnfluoiOethoxy)-2-aminopyrimidin-4- yi)-2,8-diazaspko[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluoi -l-(4-(l-methyl-lH-indazol-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-(benzo[d]isothiazol-5-yl)phenyl)-2,2i2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-(benzo[d]thiazol-6-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspii [4,5]decane-3-carboxylic acid;
(S)-8-(6-((R)-l-(4-([l,2,4]triazolo[lJ5-a]pyridin-6-yl)phenyl)-2,252-trifluoiOethoxy)-2- aminopyrimidm-4-yl)-2;8-diazaspiiO[4.5]decane-3-cavboxylic acid;
(S)-8-(2-amino-6-((R)-2;2,2-tnfluoiO-l-(4-(naphthalen-2-yl)phenyl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)"8-(2-amino-6-((R)-2,2;2-trifluoiO-l-(3'-methoxy-4'-methyl-[l,l'-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2J8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2}2-trifluoiO-l-(3'-methoxy-5'-metliyl-[l,r-bip enyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2)2,2-trifliioiO-l-(5'-methoxy-2'-meihyl-[l)r-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2J8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(3',4'-dimetlioxy-[lir-biphenyl]-4-yl)-2,2,2- tnfluoroetlioxy)pyrimidin-4-yl)-2J8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluoi -l-(3l-methoxy-4'-(pynOlidine-l-carbonyl)-[l,r- biphenyl]-4-yl)ethoxy)pyi'imidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2;2-irifluoiO-l-(4-(l-oxo-l ,3-dihydiOisobenzofuran-5- yl)phenyl)ethoxy)pyriniidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifliioi - 1 ~(4-(2-oxo- 1 ,2-dihydiOquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2>8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluoi -l-(4-(l-methyl-2-oxo-l,2-dihydi quinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.53decane-3-cai'boxylic acid; (8)-8-(2-3ηιϊηο-ό-(( )-2,2,2-ΐηί1ιιθΓθ-1-(4-(2-οχο- 1,2,3 ,4-tetrahydraquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-caiboxylic acid;
(S)-8-(6-((R)-l-(4-(iH-indazol-5-yl)phenyl)-2J2,2-tiifluoiOethoxy)-2-aminopyrimidin-4- yl)-2,8-diazaspitO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l -(4-(l,3-dimethyl-lH-indazol-5-yl)phenyl)-2,2,2- tnfluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4,5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-(l,3-dimethyl-lH-indol-5-yl)phenyl)-2J2,2- trifluoi ethoxy)pyrimidin-4-yl)-2>8-diazaspii'o[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifliioiO-l-(3,-methoxy-5,-(trifluoiOmethyl)-[l,l,-biphenyl]- 4-yl)eihoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-cai'boxylic acid;
(S)-8-(2-amino-6-((R)-l-(3'-cyano-5,-methoxy-[l,l'-biphenyl]-4-yl)-2i2)2- trifluoiOethoxy)pyi'imidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2J2,2-tnfluoi -l-(4-(2-oxo-2J3-dihydrobenzo[d]oxazol-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluoiO-l-(4-(3-methyl~lH-indol-5- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-cai'boxylic acid;
(S)-8-(6-((R)-l-(3'-acetoxy-4,-(methoxycarbonyl)-[lJl'-biphenyl]-4-yl)-2,2)2- trifluoiOethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2>2J2-trifluoiO-l -(4-(2-oxo-2H-chromen-7- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifiuoi -l-(4-(l-methyl-6-oxo-l)6-dihydiOpyridin-3- yl)phenyl)ethoxy)pyrimidin-4-yl)-2)8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4'-carboxy-3'-hydiOxy-[l)r-biphenyl]-4-yl)-2,2)2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4,5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,252-trifluoi -l-(4-(2-methoxyquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-252,2-trifluoiO-l-(4-(2-(methylthio)quinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.53decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4-(l-methyl-2-oxo-l)2J3,4-tetrahydiOquinolin-6- yl)phenyi)eihoxy)pyi'imidin-4-yl)-2J8-diazaspii'o[4.5]decane-3-carboxylic acid; (3S)-8-(2-amino-6-(2,2)2-tiifluoiO-l-(3'-fluoro-[l,l'-biphenyl]-4-yl)ethoxy)pyrimidin-4- yl)-2>8-diazaspiro[4,5]decane-3-carboxyIic acid;
(3S)-8-(2-amino-6 2,2,2-tiifluoiO-l-(3'-methoxy-[lJl'-biphenyl]-4-yl)ethoxy)pyi midin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-tiifluoro- l-(3'-fluoi -[l ,l'-biphenyl]-4-yl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2J2,2-tnfluoi -l-(3'-methoxy-[l,l ,-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2>8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2J2)2-trifluoiO-l-(3,-fluoi -5'-methoxy-[l;l'-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l -(3',5'-difluoi -[l!l'-biphenyl]-4-yl)-2>252- tiifluoiOethoxy)pyriinidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2}2-trifluoi -l-(4!-methoxy-[l}r-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2)8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-irifluot -l-(2,-methoxy-[l,l'-biphenyl]-4- yl)ethoxy)pyrimidin-4-yi)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'-(trifluoiOmethyl)-[l ,l'-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4,5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2J2J2-trifluoi -l-(3'-(tiifliioiOmethoxy)-[l,r-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8 2-amino-6-((R)-l-(3'-ethoxy-[l ,l '-bipheny^
4-y l)-2;8-diazaspiro [4.5] decane-3 -carboxylic acid;
(S)-8-(2-amino-6-((R)-2J2,2-trifluoiO-l-(3,-isopropoxy-[l,l,-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2 rifluoiO-l-(4-(pyndin-3-yl)pheiiyl)ethoxy)pyrimidin-4^ 2, 8-diazaspiro [4.5] decane-3 -carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2;2-tiifluoro-l-(4-(pyndin-4-yl)phenyl)ethoxy)pyrimidin-4-y 2, 8 -d iazaspiro[4.5 ]decane-3 - c arboxylic acid ;
(S)-8-(2-amino-6-((R)-252,2-trifluoiO-l-(4-(pyiimidin-5-yl)phenyl)ethoxy)pyrim yl)-2 , 8 - di azaspiro [4.5]decane-3 - carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4 3-methyl-lH-indazol-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-(l)3-dimethyl-lH-iiidazol-6-yl)phenyl)-2,2,2- trifluoi ethoxy)pynmidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-(253-dimethyl-2H-indazoI-6-yl)plienyl)-2,2,2- trifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4-(l-oxo-l ,253,4-tetrahydiOisoquinolin-6-- yl)phenyl)ethoxy)pynmidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2J2-ti fluoi -l-(4-(isoquinolin-6-yl)plienyl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-tiifluoiO-l-(4-(isoquinolin-7-yl)phenyl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiiO[4.5]decane-3-cat'boxylic acid;
(S)-8-(2-amino-6-((R)-l-(4'-((dimetliylamino)methyl)-[l,l,-biphenyl]-4-yl)-2)2,2- trifluoi ethoxy)pyiimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8 2-amino-6-((R)-2,2s2-trifluoi -l-(4-(quinolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro[4,5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-tiifluoro-l-(4-(quiiiolin-7-yl)phenyl)ethoxy)pyrimidin-4-yl)- 2,8-diazaspiro [4.5] decane -3 -carboxyiic acid;
(S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(4-(quinoxalin-6-yl)phenyl)ethoxy)pyrimidin-4-- yl)-2f8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R 2,2,2-trifiuoiO-l-(4-(2-methyl- 1-oxo- 1,2,3,4- tetrahydraisoquinolin-6-yl)phenyl)ethoxy)pynmidin-4-yl)-2,8-diazaspiiO[4.5]decane-3- carboxylic acid;
(S)-8-(2-amino-6-((R)-252,2-trifluoro-l-(4-(quinazolin-6-yl)phenyl)ethoxy)pyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2;2,2-trifliioi -l-(4,-fluoi -2'-metlioxy-[l,r-biphenyl]-4- yl)etlioxy)pyrimidin-4-yl)-2,8-diazaspii'o[4,5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2J2-trifluoi -l-(2'-fluoiO-3,-methoxy-[l,l'-biphenyl]-4- yl)ethoxy)pyriniidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluoiO-l-(2'-fluoiO-5'-meihoxy-[l,r-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2}8-diazaspiiO[4.5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoi -l-(4-(6-methylpyridin-3- yl)pheiiyl)ethoxy)pyrimidin-4-yl)-2>8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluo
yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)- l-(3'-carboxy-[l , 1 '-biphenyl]-4-yl)-2,2,2- trifluoi ethoxy)pyrimidin~4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-ammo-6-((R)~ 1 -(4'-carboxy-[l , r-biphenyl]-4-yl)-2,2,2- tnfluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4,5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2)2}2-irifluoro-l-(4'-piOpyl-[lJl'-biphenyl]-4-yl)ethoxy)pyrimid 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2)2,2-tnfluoro-l-(3'-(hydroxymethyl)-[l)r-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2)252-trifliioro-l -(2'-(hydroxymethyl)-[l ,1 '-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-tnfluoiO-l -(4'-isopropoxy-[l }l'-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4'-(dimethylcarbamoyl)-[l,r-biphenyl]-4-yl)-2;2,2- trifluoroethoxy)pynmidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R 2,2,2-trifluoi - 1 -(3'-(piperidine- 1 -carbonyl)-[ 1 , 1 '-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(2'-((dimethylamino)methyl)-[l5r-biphenyl3-4-yl)-2J2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)- 1 -(4'-ethyl-[l , 1 '-biphenyl]-4-yl)-2,2,2-trifluoi ethoxy)pynmidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2J2,2-trifluoro-l -(3'-hydroxy-n , 1 '-biphenyl]-4- yl)ethoxy)pyriniidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluoiO-l-(4'-hydiOxy-[l ,l ,-biphenyl]-4- yl)etboxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(2,,4,-dimethoxy-[l,l'-biphenyl]-4-yl)-2,2,2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxyIic acid; (S)-8-(2-amino-6-((R)-2,2;2-trifluoiO-l-(4,-(tnfluoiOmethyl)-[ljr-biphenyl]-4- yl)ei oxy)pyfimidin-4-yl)-258-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2J2,2-trifluoiO-l-(2*-(trifluoiOmethyl)-[l)l,-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-cai'boxylic acid;
(S)-8-(2-amino-6-((R)-l-(2',6'-difluoiO-[l,r-biphenyl]-4-yl)-2J2)2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)~ 1 -( ,&-dimet y\~[\ , 1 ,-biphenyl]-4-yl)-2J2,2- tiifluoiOethoxy)pyiimidin-4-yl)-2J8-diazaspitO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(3'34,-dimethyl-[l,l,-biphenyl]-4-yl)-2,2,2- trifluoiOethoxy)pyrimidin-4-yl)-2>8-diazaspiro[4.5]decane-3-cai'boxylic acid;
(S)-8-(2-amino-6-((R)-l-(4'-(tert-butyl)-[l5l'-biphenyl]-4-yl)-2,2,2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2)2,2-trifluoiO-l-(4'-isopi pyl-[l,l,-biphenyl]-4- yl)ethoxy)pyrimidin-4-yi)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(8)-8-(2-3ηιΐηο-6-^)-2,252-η·ίΑυοΐΌ-1-(3'-ί8ορ^1-[1 ,1'-Μρ1^1]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(S>8-(2-amino-6-((R)-l-(3,,4'-dichloiO-[l}r-biplienyl]-4-yl)-2,2,2- ti'ifluoiOethoxy)pynmidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2)2-trifluoiO-i-(4'-(trifl oiOmethoxy)-[l!r-biphenyl]-4- yl)ethoxy)pyrimidin-4-yi)-258-diazaspiro[4.5]decane-3-carboxyIic acid;
(S)-8-(2-amino-6-((R)-l-(2'J3'-dimethyl-[l}r-biphenyl]-4-yl)-2,2,2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2)2;2-trifluoro-i-(3, J4'55,-trifluoi -[l)r-biphenyl]-4- yl)ethoxy)py imidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxyiic acid;
(S)-8-(2-amino-6-((R)- 1 -(4'-chloro-2,-methyl-[l , 1 '-bip enyl]-4-yl)-2,2,2- tnfluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-ammo-6-((R)-l-(3',5'-dimethyl-[l,l'-biphenyl]-4-yl)-2,2,2- trifluoi ethoxy)pyi'imidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)- 1 "(3'54'-difluoiO-[l , l,-biphenyl]-4-yl)-2,2,2- trifluoiOethoxy)pyrimidin-4-yl)-258-diazaspiiO[4.5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-l-(2'J5'-din ethyl-[l,l'-bip enyl]-4-yl)-252,2- trifluoiOethoxy)pyi*imidii>4-yl)-2,8-diazaspiiO[4,5]decane-3-carboxyIic acid;
(S)-8-(2-ammo-6-((R)- 1 -(4'-butyl~[l , 1 ,-biphenyl]-4-yl)-2)2)2-trifluoiOethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2}2-trifluoro-l-(3,-fluoro-4'-methyl-[l)l,-biphenyl]-4- yl)ethoxy)pyrimidin-4-yI)-2,8-diazaspiro[4,5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-iiifluoi -l-(4'-(methylsulfonyl)-[l>l,-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluoiO- 1 -(4'-methyl-[l ,1 '-biphenyl]-4- yi)ethoxy)pynmidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-252,2-trifluoiO-l-(3'-methyl-[l,l'-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decaiie-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4,-chloiO-[l,r~biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yi)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-i-(4-(benzofuran-3-yl)phenyl)-2J2,2-trifluoi ethoxy)pyrimidin-4- yl) -2 , 8 -diazaspiro [4, 5 ] decane- 3 -carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluoiO-l-(5,-fluoiO-2'-methoxy-[l,l'-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4,5]decane-3-cai,boxylic acid;
(S)-8-(2-aniino-6-((R)-2)2)2-trifluoiO-l-(4-(2-oxochiOman-7- yl)p enyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4-(l,2,3,4-tetrahydiOquinoxalin-6-yl) phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6~((R)-l -(3,4-dihydroquinazolin-6^
yl)-2,8-diazaspiro[4,5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2)2,2-trifluoi -l-(l,2)3J4-tetrahydiOquinazolin-6-yl)ethoxy) pyrimidin-4-y!)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l 4-bromophenyl)-2,2,2-trifluoiOethoxy)pyrimidin-4-yl)-258- diazaspiiO[4,5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-tiifluoro-l-(naphthalen-2-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid; 9-(2-Amino-6-((R)-l-(4-chloiO-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2)2,2- trifluoiOethoxy)pynmidin-4-yl)-3,9-diazaspiro[5.5]undecane-2-carboxylic acid;
(S)-8-(2-Amino-6-((4-(3-methyl-lH-indazol-6-yl)phenoxy)methyl)pyrimidin-4-yl)-2,8- di azaspiro [4.5 ] decane-3 - carboxylic acid ;
(S)-8-(2-amino-6-((5-chloro-3'-(methylsidfonyl)-[l)r-biphenyl]-2-yl)methoxy)pyrimidin- 4-yl)~2, 8 -diazaspiro [4.5]decane-3 -carboxylic acid;
(S)-ethyl 8-(2-amino-6-((R)-l-(4-(benzo[d]thiazol-6-yl)phenyl)-2i2,2- trifluoi'oethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-cai'boxylate;
(S)-ethyl 8-(6-((R)-l-(4-(lH-indazol-5-yl)plienyl)-2,2,2-tnfluoi ethoxy)-2- aminopyrimidin-4-yi)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoiO-l -(3'-methoxy-4'-(pyriOlidine- 1 -carbonyl)- [l5 -biphenyl]-4-yl)etlioxy)pyrimidin-4-yl)-2}8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloiO-4'-nitiO-[i,l,-biphenyl]-2-yl)-2,2)2- tnfluoroethoxy)pyrimidin-4-yl)-2,8-diazaspii'o[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4-(benzo[d]isothiazol-5-yl)phenyl)-232,2- ttifliioiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)- 1 -(4-(benzo[d]isothiazol-6-yl)phenyl)-2,2,2- ti'ifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4,5]decane-3-cai'boxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(3',4'-dimethoxy-[l,l,-biphenyl]-4-yl)-2>2,2- ti'ifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-triiluoiO-l-(4-(l-methyl-2-oxo-l52-dihydi quinolin-6- yl)phenyl)ethoxy)pyi'imidin-4-yl)-2(8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l -(5-chloro-[l , 1 '-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(3'-amino-5-chloi -[l,r-biphenyl]-2-yl)-2,2,2- tiifluoroethoxy)pyiimidin-4-yl)-2)8-diazaspiiO[4,5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifliioiO-l-(3'-(metliylsulfonyl)-5-piOpyl-[l,l'- bipbenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4-(l ,3-dimethyl-l H-mdoi-5-yl)phenyl)-2,252- trifluoi ethoxy)pyrimidin-4~yl)-2,8-diazaspiiO[4.5]decane-3-cai'boxylate; (S)-ethyl 8-(6-((R)-l -(3'-acrylamido-5-chloro-[l , 1 '-biphenyl]-2-yl)-2,2,2- trifluoiOethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2}2,2-ti'ifluoro-l-(3,-fluoiO-4,-methoxy-[l,l"-biphenyl]-4- y l)ethoxy )pyrimidi n-4 -y 1) -2, 8 -d iazaspi ro [4.5] dec ane- 3 -c arb oxy late;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoiO- 1 -(4-(l -methyl-6-oxo- 1 ,6-dihydiOpyridin-3- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4,5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-252}2-trifluoiO-l-(4-(2-oxo-l,2)3,4-tetrahydroquinolin-6- yl)phenyl)eihoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoi -l -(4-(2-oxo-l,2-dihydroquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2J8-diazaspiro[4.5]decane-3-carboxyIate;
(S)-ethyl 8-(2-amino-6-((R)-2,2}2-trifluoiO-l~(3'-(methylsulfonyl)-5-((E)-piOp-l-en-l- yl)-[l,l'-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-cai,boxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoiO-l-(4-(3-methyl-lH-pyrazol-l-yl)-[l Jl'- biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyI 8-(2-ammo-6-((R)-l-(4^
yl)~2,2,2-trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoi -l~(3'-(methylsulfonyl)-4-pi pyl-[l}r- biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2)2-trifluoi -l-(3,-(methylsulfonyl)-4-((E)-prop-l-en-l- yl)-[l, -biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspitO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-3,-(ethylsulfonyl)-[lsr-biphenyl]-2-yl)-2,2s2- tnfluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4,5]decane-3-carboxylate;
(S)-eihyl 8-(2-amino-6-((R)-l-(5-chloiO-3'-(piOpylsulfonyl)-[l,l'-biphenyl]-2-yl)-2,2)2- trifluoiOethoxy)pyrimidin-4-yl)-2)8-diazaspiro[4.5]decane-3-carboxylate;
CS)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-3,-(butylsulfonyl)-[ l,l'-biphenyl]-2-y trifluoiOethoxy)pyiimidin-4-yl)-2,8-diazaspiiO[4,5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2)2-trifluoiO-l -(4-(l-oxo-l ,3-dihydroisobenzofuran-5- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2J2)2-trifluoi -l-(4-(2-methoxyquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-l -(5-chloro-3'-(hydroxymethyl)-[l ,1 '-biphenyl]-2-yI)-2,2,2- trifliioi ethoxy)pyrimidin-4-yl)-2)8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chlora-3'-(2-oxopyn lidin-l-yl)-[l)l,-biphenyl]-2"yl)- 2J2,2-ti-ifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-cai,boxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloiO-3'-(3-methyl-2-oxoimidazoHdin-l-yl)-[l,l'- biphenyl]-2-yl)-2,2,2-trifluoi ethoxy)pynmidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)- l-(4-chloiO-3,-(methylsulfonyl)-[l,l'-biphenyl]-2-yi)-2)2,2- trifluoiOethoxy)pyrimidm-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloiO-3'-(methylsulfonamido)-[l,r-biphenyl]-2-yl)- 2,2,2-trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4,5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(2-bromo-5-chlorophenyl)-2,2,2- trifluoioethoxy)pynmidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoiO-l-(4-(l -methyl-2-oxo-l, 2,3,4- tetrahydi qiunolin-6-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2J2-trifluoro- 1 -(4-(2-(methy lthio)quinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(2,5-dibromophenyl)-2,2,2-trifliioiOethoxy)pyrimidin-4- yl)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(6-((R)-l-([l,l':4'>r,-terphenyl]-2,-yl)-2,2!2-trifluoiOethoxy)-2- aminopynmidin-4-yl)-2,8-diazaspiiO[4.5Jdccane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l -(2'-(ethoxycarbonyl)-3-(3-methyl-l H-pyrazol- 1 -yl)-[l , 1 '- biphenyl]-4-yl)-2J2,2-trifluoiOethoxy)pyi'imidin-4-yl)-2,8-diazaspii [4.5]decane-3-cai'boxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(3'-(ethoxycarbonyl)-3-(3-methyI-lH-pyrazol-l-yl)-[l,l'- biphenyl] -yl)-2J2,2-trifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4,5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)- 1 -(4'-(ethoxycarbonyl)-3-(3-methyl-lH-pyrazol- 1 -yl)-[l , 1 '- biphenyl]-4-yl)-2,2,2-ti'ifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(2,6-dibi mophenyl)-2,2,2-trifluoiOethoxy)pyrimidin-4- y^^jS-diazaspiro^.SJdecane-S-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(3';5-dichloiO-[l,l,-biplienyl]-2-yl)-2)2,2- ti,ifliioi'oethoxy)pyrimidin-4-yl)-2J8-diazaspiiO[4.5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloiO-3'-methyl-[l ,l'-biphenyl]-2-yl)-2f2)2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-cai'boxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloi ^
ti'ifluoroethoxy)pyi-imidin-4-yl)-258-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluolΌ-l-(3-(3-methyl-lH-pyr zol-l-yl)-4,- (methylthio)-[l,l '-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4-chloro-[l,r-biphenyl]-2-yl)-2,2,2- trifluoi ethoxy)pyiimidin-4-yl)-2>8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-eihyl 8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4'-methyl-3-(3-methyl-lH-pyrazol-l-yl)- [ 1 , -bipheny 1] -4 -y l)ethoxy)pyrimid i n- 4-yl) -2, 8 -diazaspiro [4.5 ]decane -3 -cavboxy late;
(S)-ethyl 8-(2-amino-6-((R)-2;2;2-trifluoro-l-(3'-methyi-3-(3-methyl-lH-pyrazol-l -yl)- [1,1 '-biphenyl]-4-yl)ethoxy)pyrimidin-4-yI)-2,8-diazaspiro[4.53decane-3-cai-boxylate;
(S)-ethyl 8-(2-amino-6-((R)"l-(3',4'-dichlom-3-(3-methyl-lH-pyiazol-l-yl)-[l,l'- biphenyl] -yl)-2}2)2-tnfluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-cai,boxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4-chloro-2-(2-oxopynOlidin-l-yl)phenyl)-2;2,2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-cai'boxylate;
ethyl 8-(2-amino-6-((R)- 1 -(4-chloro-2-(3-methy 1- 1 H-pyrazol- 1 -yl)phenyl)-2,2,2- trifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4,5]decane-3-cai'boxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4-chloiO-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoiOethoxy)pyrimidin-4-yl)-2}8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,252-trifluoiO-l -(3'-methoxy-[l ,r-biphenyl]-4- yl)ethoxy)pyi'imidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2)2,2-trifluoi - 1 -(4-methoxy-2-(3 -methyl- 1 H-pyrazol- 1 - yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoi -l -(3'-ί1ιιοΐΌ-[1 ,1 '-biphenyl]-4- yI)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(3',4,-dimethyl-3-(3-methyl-lH-pyrazol-l-yl)-[l>l'- biphenyl]-4-yl)-252,2-tiifluoiOethoxy)pywmidin-4-yI)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4-ethyl-2-(3-methy 1-1 H-pyrazol- 1 -yl)phenyl)-2,2,2- trifluoiOethoxy)pyi'imidin-4-yl)-2,8-diazaspiro[4,5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2}2,2-trifluoro-l-(2-(3 -methyl- lH-pyrazol-1 -yl)-4- piOpylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4,5]decane-3-catboxyiate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4-butyl-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- †rifluoi ethoxy)pynmidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxy!ate;
(S)-ethyl 8-(2-amino-6-((R)-i-(5-(ethoxycarbonyl)-2-(3-methyI-l H-pyrazol-l- yl)phenyi)-2,2,2-ti,ifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)- 1 -(4-(et oxycarbonyl)-2-(3-methyl- 1 H-pyrazol- 1 - yl)phenyl)-2,2)2-ti-ifluotOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-((E)-3-ethoxy-3-oxopi p-l-en-l-yl)-2-(3-methyl-lH- pyrazol-l-yl)ph.enyl)-2,232-trifluoiOethoxy)pyi,imidin-4-yl)-2)8-diazaspiro[4.5]decane-3- carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-(3-ethoxy-3-oxopropyl)-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoiOethoxy)pyrimidin-4-yl)-2>8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-l-(6-methyl-2-(3-methyl-lH-pyrazol-l- yl)pyridin-3-yl)ethoxy)pyrimidin-4-yl)-2}8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8~(2-ammo-6-((R)-252,2-trifliioro- 1 -(2-(3 -methyl- 1 H-pyrazol- 1 -yl)-5-((E)-prop- 1 -en- 1 -yl)phenyl)etlioxy)pyi"imidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)- 1 -(3',4!-dimethyl-4-(3 -methyl- 1 H-pyrazol- 1 -yl)-[l , 1 !- biphenyl]-3-yl)-2,2,2-trifIuoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-tnfluoro-l-(2-(3-methyl-lH-pyrazoi-l -yl)-5- piOpylphenyl)ethoxy)pyrimidin-4-yI)-2,8-diazaspii [4.5]decane-3-carboxyiate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-ethyi-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2J2,2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-b¾tyl-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoiOethoxy)pyrimidin-4-yl)-2J8-diazaspiiO[4.5]decane-3-carbox late;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-†rifmoiO- 1 -(2-(3 -methyl- 1 H-pyrazol- 1 -yl)-5- vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-((E)-buM -en-l-yl)-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2;2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4-ch]oiO-2-(l-methyl-lH-pyrazol-3-yl)phenyl)-2,2,2- ti'ifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-cai,boxylate; (S)-ethyl 8 2-amino-6-((R)-2,2)2-trifluoro- l-(2-(l-methyl-lH-pyrazol-3- yl)phenyl)ethoxy)pyrimidin-4-yl)-2J8-diazaspiiO[4,5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4-(l,3-dimethyl-lH-indazol-6-yl)phenyl)-252,2- trifluoiOethoxy)pyi,imidin-4-yl)-2,8-diazaspiiO[4,5]decane-3-cai,boxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4-(2,3-dimethyl-2H-indazol-6-yl)phenyl)-2,2,2- trifluoi ethoxy)pyrimidin-4-yl)"2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2J2-trifluoro-l -(4-(l -oxo-15233,4-tetrahydiOisoquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-cai'boxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4-(isoqmnolin-6- yl)phenyl)ethoxy)pyi'imidin-4-yl)-2;8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4-(3-ethoxy-3-oxopropyl)-2-(3-methyl-lH-pyrazol-l- yl)plienyl)-2,2,2-trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoi -l -(4-(isoquinolin-7- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)- 1 -(5-(4-ethoxy-4-oxobutyl)-2-(3-methyl- 1 H-pyrazol- 1 - yl)phenyl)-2,2t2-tiifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4-(4-ethoxy-4-oxobutyl)phenyl)-2,2,2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)- 1 -(4-(4-ethoxy~4-oxobutyl)-2-(3-methyl- 1 H-pyrazol- 1 - yl)phenyl)-2,2)2 rifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R l-(3,-cyano-3-(3-methyl-lH-pyrazol-l-yl)-[l,l'-biphenyl]-4- yl)-2}2,2-trifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylaie;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloiO-3'-cyano-[ljr-biphenyl]-2-yl)-2)252- influoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxy!ate;
(S)-ethyl 8-(2-amino~6-((R)- l-(5-chloro-3'-methoxy-[l ,l,-biphenyl]-2-yl)-2!2,2- ti,ifliioi ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l -(5-chIoi -3,-sulfamoyl-[l,l,-bipheiiyl]-2-yl)-2;2,2- trifluoiOethoxy)pyi'imidin-4-yl)-2,8-djazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)- 1 -(5-chloi -3'-hydroxy-[l , 1 '-biphenyl3-2-yl)-2,252- ti'iflitoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)- 1 -(5-chloi -3'-(methylsulfonyl)-[l , 1 '-biphenyl]-2-yl)-2,2,2- trifluoiOethoxy)pynmidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-araino-6-((R)-l -(3,-(aminomethyl)-5-chloiO-[lJl'-biphenyl]-2-yl)-2,252- ti'ifluoiOetlioxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-cai'boxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2;2-trifluoi -l-(4-(quinolin-6-yl)phenyl)ethoxy)pyrimidin- 4-yi)-2,8-diazaspiiO[4,5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,252-ti1fluoi -l-(4-(quinoIin-7-yI)phenyl)ethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2)2-trifluoiO-l-(4'-isopiOpoxy-3-(3-methyl-lH-pyrazol-l- yi)-[l,l'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2s2)2-trifluoro- 1 -(4-(quinoxalin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(6-((R)-l-(4l-(acetamidomethyl)-3-(3-methyl-lH-pyrazol-l-yl)-[l, l '- biphenyl]-4-yl)-2J2,2-ti,ifluoiOethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3- carboxylate;
(S)-ethyl 8-(6-((R)-l-(4,-(2-acetamidoethyl)-3^3-methyl-lH-pyrazol-l-yl)-[i,r- biphenyl]-4-yl)-2,2}2-trifluoiOethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3- carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2!2-{nfluoi -l-(2-(3-methyl-lH-pyrazol-l-yl)-4-(quinolin- 7-yl)phenyl)ethoxy)pyrimidin-4-yl)-2J8-diazaspiro[4.5]decane-3-cai'boxylate;
(S)-ethyl 8-(2-amino-6-((R)-2J2)2-trifluoro- 1 -(4-(2-methoxypyridin-4-yl)-2-(3-methyl- lH-pyrazol-l -yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(6-((R)-l-(4-(lH-indol-6-yl)-2-(3-methyl-lH-pyrazoi-l-yl)phenyl)-252,2- tnfluoiOethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloiO-3'-(ethoxycavbonyl)-[l ,l '-biphenyl]-2-yl)-2,2,2- ti'ifliioiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
2'-((R)-l-((2-amino-6-((S)-3-(ethoxycarbonyl)-2,8-diazaspiro[4.5]decan-8-yl)pyrimidin- 4-yl)oxy)-2,2)2-trifluoroethyl)-5'-chloiO-[l , 1 '-biphenyl]-3-carboxylic acid;
(S)-ethyl 8-(6-((R)-l -(3'-(acrylamidomethyl)-5-chloiO-[l,l'-biphenyl]-2-yl)-2)2)2- trifluoroethoxy)-2-aminopyrimidin-4'-yl)-2,8-diazaspiiO[4,5]decane-3-carboxylate; (S)-ethyl 8 2-amino-6-((R)-l 3'-carbamoyl-5-chloro-[l,r-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pynmidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-4,-(methylsulfonyl)-[lJl'-biphenyl]-2-yl)-2,2,2- trifliiotOethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)- 1 -(5-chloro-4'-sulfamoyl-[l ,1 ,-biplienyl]-2-yl)-2,2,2- trifluoroethoxy)pyiimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-caiboxylate
(S)-ethyl 8-(2-amino-6-((R)-l-(2'-(eihoxycarbonyl)-4-(3-methyl-lH-pyrazol-l -yl)-[l>r- biphenyl]-3-yl)-2,2,2-tiifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l -(3'-(ethoxycarbonyl)-4-(3-methyl- lH-pyrazol-1 -yl)-[l ,1'- biphenyl]-3-yl)-2,2,2-tiifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4,-(ethoxycarbonyl)-4-(3-methyl-lH-pyrazol-l-yl)-[l Jl'- biphenyl]-3-yl)-2,2;2-ti,ifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(3S)-ethyl 8-(2-amino-6-((lR)-l-(4-(l,2-dihydi xyethyl)-2-(3-methyl-lH-pyrazol-l - yl)phenyl)-2,2,2-trifliioi ethoxy)pydmidin-4-yl)-2,8-diazaspiro[4.5]decane-3-cai,boxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4'-(aminomethyl)-3-(3-methyl-lH-pyrazol-l-yl)-[l>l'- biphenyl]-4-yl)-2,2,2-trifluoiOethoxy)pynmidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-et yl 8-(2-amino-6-((R)-l-(3'-((E)-3-ethoxy-3-oxopiOp-l-en-l-yi)-4-(3-methyl-lH- pyrazol - 1 -yl)- [ 1 , l '-biphenyl] -3 -y l)-2,2,2-trifluoi ethoxy)pyrimidin-4-yl)-2) 8 - diazaspiro [4.5]decane-3 -carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4'-((E)-3-ethoxy-3-oxopiOp-l-en-l-yl)-4-(3-methyl-lH- pyrazol-l-yl)-[l5 -biphenyl]-3-yl)-2,2,2-trifluoroethoxy)pyiimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(3'-(3-ethoxy-3-oxopiOpyl)-4-(3-nietliyl-lH-pyrazol-l-yl)- [l} -biphenyl]-3-yl)-252,2-trifliioiOethoxy)pyrimidin-4-yl)-2J8-diazaspiro[4.5]decane-3- carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4,-(3-ethoxy-3-oxopropyl)-4-(3-methyl-lH-pyrazol-l-yl)- [l, -biphenyl]-3-yl)-2J2>2-trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3- carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2!2,2-irifluoiO-l-(3'-fluoro-3-(3-methyl-lH-pyrazol-l-yl)- [lJi'-biphenyl]-4-yl)ethoxy)pynmidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoiO- 1 -(2-(3 -methyl- 1 H-pyrazol- 1 -yl)-4-(quinolin- 6-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-cai*boxylate;
(3S)-ethyl 8-(2-amino-6-((lR)-2f2J2-trifluoro-l-(2-(3-methyi-lH-pyrazol- l-yl)-4-(2-oxo- l,3-dioxolan-4-yl)phenyl)et oxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyi 8-(2-amino-6-((R)-2,2,2-trifluoro-l -(4-(2-methyl-l -oxo- 1,2,3,4- tetrahydroisoquinolin-6-yl)plienyi)ethoxy)pyiimidin-4-yl)-2,8-diazaspii [4,5]decane-3- carboxylate;
(S)-ethyl 8-(6-((R)-l -(4-(acetamidomethyl)-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2s2- trifluoiOetlioxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-cai'boxylate;
(3S)-ethyl 8-(2-amino-6-((lR)-2,2)2-trifliioro-l-(3-(3-metbyl-iH-pyrazol-l-yl)-4,-((2-((2- oxotetrahydiOfuimi-3-yl)thio)ethyl)carbamoy
diazaspiro[4.5]decane-3-cavboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(3)4-dimetllyl-3M-(metllylsulfonyl)-[l)l,:3 1"-terphenyl]-4,- yl)-232,2-tiifluoroethoxy)pyiimidin-4-yl)-2J8-diazaspiro[4.5]decatie-3-cai'boxylaie;
(S)-ethyl 8-(2-amino-6-((R)-2)2,2-tnfluoro-l-(3'-(methylsulfonyl)-5-(qmnolin-6-yl)-[l,r- bip3ienyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2)2)2-tnfluoiO-l-(4'-(hydiOxymethyl)-3'-methyl-4-(3-methyl- lH-pyrazol-l-yl)-[lj -biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)-2J8-diazaspiro[4.5]decane-3- carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2J2,2-trifiuoro-l -(3'-(hydiOxymethyl)-4,-methyl-4-(3-methyl- lH-pyi,azol-l -yI)-[l)r-biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2J2-trifluoiO-l-(4'-(methoxycarbonyl)-4-(3-methyl-lH- pyrazol-l-yl)-[l, -biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate;
3'-((S)-l-((2-amino-6-((R)-3-(ethoxycarboiiyl)-2,8-diazaspiiO[4,5]decan-8-yl)pyrimidin- 4-yl)oxy)-2,2,2-trifluoi ethyl)-4,-(3-metliyl-l H-pyrazol- 1 -yl)-[l , 1 *-biphenyl]-4-carboxylic acid;
(S)-ethyl 8-(2-amino-6-((R)-2,2)2-trifluoiO-l-(2-(3-methyl-lH-pyrazol-l-yl)-4-(l-oxo- l ,3-dihydiOisobenzofuran-5-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3- carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-l-(4-(quinazolin-6- yl)phenyI)ethoxy)pyi'imidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro- 1 -(2-(3-methyl- 1 H-pyrazol- 1 -yl)-4- (pyrimidin-5-yl)phenyl)ethoxy)pyrimidin-4-yl)-2J8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(3,,4,-difluoro-3-(3-methyl-lH-pyrazol-l-yl)-[lir- biphenyl]-4-yl)-2,2,2-trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate
(S)-ethyl 8-(2-amino-6-((R)-l-(4'-chloi -3-(3-methyl-lH-pyrazol-l-yl)-[l5l,-biphenyl]-4 yl)-2,2,2-ti'ifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-e†hyl 8-(2-amino-6-((R)-l-(5-chloiO-[l3l'-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspitO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4'-chloiO-4-(3-methyl-lH-pyrazol-l-yl)-[l,l*-b^ yl)-2>2,2-trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4,5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(3'i4'-difluoiO-4-(3-methyl-m-pyrazol-l-yl)-[lJll- biphenyl]-3-yl)-2,252-triflnoroethoxy)pyrimidin-4-yl)-2,8-diazaspii [4,5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2J2;2-trifluolΌ-l-(4-(3-methyl-lH-pyrazol-l-yl)-[l)l,- biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)-2)8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-ammo-6-((R)- 1 -(3,,4'-dichlorO"4-(3-methyl- 1 H-pyrazol- 1 -yl)-[l ,1 biphenyl]-3-yl)-2,2,2-tnfluoiOethoxy)pyrirnidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-232,2-trifluoro-l-(3,-fluoi -[l ,l,-biphenyl]-2- yl)ethoxy)pyrimidin-4-yl)-2)8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoi - 1 -(2- (3 -methyl- 1 H-pyrazol- 1 -yl)-5- (pyriniidin-5-yl)phenyl)ethoxy)pynmidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amίno-6-((R)-l-(4 5-dichloIΌ-3,-fluol -[lJl'-biphenyl]-2-yl)-2,2!2- tnfluoiOethoxy)pynmidin-4-yl)-2,8-diazaspii'o[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloiO-3'-ethoxy-[l5l'-biphenyl]-2-yl)-2,2J2- trifluoroethoxy)pyi'imidin-4-yl)-258-diazaspii [4.5]decane-3-cafboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(3',5-dichloro-4'-ethoxy-[l,l'-biphenyl]-2-yl)-2)2J2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-ammo-6-((R)-l-(3 5-dichloro-5'-fluoro-[l,r-biphenyl]-2-yl)-2,2!2- trifiuoiOethoxy)pyrimidin-4-yl)-2J8-diazaspii [4.5]decane-3-carboxylate; (S)-etliyl 8-(2-amino-6~((R)- 1 -(3'-(ter†-butyl)-5-chloro-[l ,1 '-bi heny - -yl)-!^^- trifluoroethoxy)pyrimidin-4-yl)-2J8-diazaspiiO[4.5]decane-3-cai,boxylate;
(S)-ethyl 8-(2-amino-6-((R)- l-CS'^-dichloiO-S'-itrifluoi methy -tl ,1 '-biphenyl]-2-yl)- 2,232-trifluoiOethoxy)pyiimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8 2-amiiio-6-((R)-l-(5-chloi -3'-fliioro-5'-(trifluoi methyl)-[l)l,-biphenyi]-2- yl)-2,2,2-trifluoiOethoxy)pyrimidin-4-yl)-2)8-diazaspiiO[4.5]decane-3-cai'boxylate;
(S)-ethyi 8-(2-amino-6-((R)- 1 -(3 '-chlora-[l , 1 '-biphenyl3-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chlora-3'-methoxy-[l,l*-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2J8-diazaspii [4.53decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)- l-(5-chlora-3'-isopiOpoxy-[l ,1 ,-biphenyl]-2-yl)-2,2!2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-cai'boxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(3'J5-dichloro~4,-methyl-[l ,l'-biphenyl]-2-yl)-2,252- trifluoroethoxy)pynmidin-4-yl)-2,8-diazaspii'o[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(3,,5-dichloiO-4,-isopi poxy-[lJl'-biphenyl]-2-yl)-2)2,2- ti'ifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l -(5-chloro-3'-fl oro-4'-isopi poxy-[i, l '-biphenyl]-2-yl)- 2;2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l -(4, )5-dichloiO-3'-(trifluoiOmethyl)-[l,l,-biphenyl]-2-yl)- 2,2,2-ti'ifluoroethoxy)pyiimidin-4-yl)-2;8-diazaspiro[4,5]decane-3-carboxylaie;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloi -3,-fluoiO-[l,l,-biphenyl]-2-yl)-2i2,2- trifluoiOethoxy)pyrimidin-4-yl)-2J8-diazaspiro[4.53decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l -(4, J5-dichloiO-3'-meihyl-[l,l,-biphenyl]-2-yl)-2,2)2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)- 1 -(S'^-dichloi ^'-Ctrifluoromethy -fl 5l '-biphenyl]-2-yl)- 252,2-trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloi -3*i5,-difluoro-[ljr-biphenyl]-2-yl)-2J2 trifluoi ethoxy)pynmidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(3')5-dichloro-4,-fluoro-[l,l'-biphenyl]-2-yl)-2,2,2- trifluoi ethoxy)pyrimidin-4-yl)-2J8-diazaspiro[4.5]decane-3-cai'boxylate; (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-3 4,-difluoro-[lJl'-biphenyl]-2-yl)-2,2,2^ trifluoiOethoxy)pyiimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-octyl 8-(2-amino-6-((R)-l-(4-chloiO-2-(3-methyl-lH-pyiazol-l-yl)phenyl)-2,2;2- trifluoi ethoxy)pyrimidin-4-yl)-2J8-diazaspii [4.5]decane-3-carboxylate;
(S)-cyclopentyl 8-(2-amino-6-((R)-l-(4-chloiO-2-(3-methyl-lH-pyrazol-l-yl)phenyl)- 2,2!2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4,5]decane-3-carboxylate;
(S)-pentyl 8-(2-amino-6-((R)-l-(4-chloiO-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifluoiOethoxy)pynmidin-4-yl)-2}8-diazaspiro[4.53decane-3-carboxylate;
(S)-cyclohexyl 8-(2-amino-6-((R)- 1 -(4-chloro-2-(3-metfayl- lH-pyrazol- 1 -yl)phenyl)- 232)2-irifluoiOethoxy)pyrimidin-4-yl)-2)8-diazaspii [4.5]decane-3-carboxylate;
(S)-propyl 8-(2-amino-6-((R)-l -(4-chloi -2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2J232- ti'ifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-cai'boxylate;
(S)-neopentyl 8-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyrazol-l-yl)plienyl)-252J2- trifliioiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
(S)-butyl 8-(2-amino-6-((R)-l-(4-chloiO-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2}2,2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-isopropyl 8-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH-pyiazol-i-yl)phenyl)-2i2,2- trifluoroethoxy)pynmidin-4-yl)-2>8-diazaspiro[4.5]decane-3-carboxylate;
(S)-tert-butyl 8-(2-amino-6-((R)-l-(4-chloi -2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2!2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
(S)-tert-butyl 8-(2-amino-6-((R)-2,2,2-trifluoiO- 1 -(2-(3-methyl- 1 H-pyrazol- 1 -y l)-4- piOpylphenyl)ethoxy)pyrimidin-4-y!)-2s8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-2-(dimethylamino)etliyl 8-(2-amino-6-((R)-l-(4-chloi -2-(3-methyl-lH-pyrazol-l - yl)phenyl)-2,2,2-tn¾ioroethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-2-(dimethylamino)-2-oxoethyl 8-(2-amino-6-((R)-l-(4-chloro-2-(3-methyl-lH- pyrazol-l-yl)phenyl)-2,2)24rifluoiOethoxy)pyrimidin-4-yl)-2;8-diazaspiro[4.5]decane-3- carboxylate;
(S)-2-(((R)-2-amino-3-methylbutanoyl)oxy)ethyl 8-(2-amino-6-((R)- 1 -(4-chloro-2-(3- methyl-lH-pyrazol-l-yl)phenyl)-2J2,2-trifluoiOethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate; and (3S)- 1 -(pivaloyloxy)ethyl 8-(2-amino-6-((R)- 1 -(4-chioro-2-(3-methyl- 1 H-pyrazol- 1 - yl)phenyl)-2,2,2 rifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate; or a pharmaceutically acceptable salt of any of the aforementioned.
122. The compound of claim 1 selected from:
(S 8-(2-amino-6-((R)-l-(3 4'-dimethyl-3-(3-methyl-lH-pyrazol-l-yl)-[l,l'-biphenyl]-4- yl)-2,2)2-trifluoi ethoxy)pyrimidin-4-yl)-2J8-diazaspiro[4,5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l -(3'-chloiO-3-(3-methyl-lH-pyrazol-l-yl)-5'-(trifluoromethyl)- [lj -biphenyl]-4-yl)-252,2-trifluoiOethoxy)pyiimidin-4-yl)-2}8-diazaspiro[4.5]decane-3- carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(3'-chloi -4,-ethoxy-3-(3-methyl-lH-pyrazol-l-yl)-[l5r- biphenyl]-4-yl)-2J2)2-tiifluoiOethoxy)pyrimidin-4-yl)-258-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2)2J2-trifluoro-l-(3-(3-methyl-lH-pyrazol-l-yl)-3'- (trifluoiOmethyl)-[l,r-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3- carboxylic acid;
(8)-8 2-3ηιϊηο-6-^)-1-(3'-ϋ1ι1οΐΌ-5·-Μ6 1-3-(3··ιη6 1-1Η^ι-αζοί-1^1)-[1,Γ- biphenyl] -yl)-2J2,2-tnflxioi ethoxy)pyrimidin-4-yl)-258-diazaspiiO[4.5]decane-3-carboxyiic acid;
(S)-8-(2-ammo-6-((R)-ί-(4l-chloIΌ-3,-fluolΌ-3-(3-meth l-lH-pyrazol-l -yi)-[l,l,- biphenyl] -yl)-2J2,2-trifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(3'-ethoxy-3-(3-methyl-m-pyrazol-l -yl)-[l)l'-biphenyl] 2,2)2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluoi -l-(3'-fluoro-4,-methyl-3-(3-methyl-lH-pyrazol-l- yl)-[l>l'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid
(S)-8-(2-amino-6-((R)-l-(3'-chloiO-4'-fiuoiO-3-(3-methyl-lH-pyrazol-l-yl)-[l}l'- biphenyl]-4-yl)-2,2,2-ti fluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-irifluoro-l-(3-(3-methyl-lH-pyrazol-l-yl)-3'- (ti fluoromethoxy)-[l, -biphenyl]-4-yl)ethoxy)pyi midin-4-yl)-2}8-diazaspiiO[4.5]decane-3- carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(3^5'-dimethy^^
yl)-2,2,2-tnfluoroeihoxy)pyrimidin-4-yI)-258-diazaspiro[4,5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(3',4'-difl oiO-3-(3-methyl-lH-pyrazol-l-yl)-[lir-biphenyl]-4- yl)-2,2)2-trifluoiOethoxy)pynmidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxyiic acid;
(S)-8-(2-amino-6-((R)-l-^5'-difluoi^^^
yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-cai'boxylic acid;
(S)-8-(2-amino-6-((R)-2J2)2-tnfluoro-l-(4'-fluoi -3-(3-methyl-lH-pyrazol-l-yl)-3'- (trifliioi methyl)-[i, -biphenyl]-4-yl)ethoxy)pyi'imidin-4-yl)-2,8-diazaspiiO[4.5]decane-3- carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluoi -l-(3'-fiuoiO-4'-isopi poxy-3-(3-methyl-lH- pyrazol-l-yl)-[l,l,-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2J8-diazaspiiO[4,5]decane-3- carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(3,-ethoxy-5'-fluoiO-3-(3-methyl-lH-pyrazol-l-yl)-[l,r- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyi'imidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(3'-(tert-b tyl)-3-(3-methyl-lH-pyrazol-l -yl)-[l,l'-biphenyl]-4- yl)-2;2,2-trifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxyUc acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluoiO-l-(4'-fluoiO-3,-methyl-3-(3-methyl-lH-pyrazol-l- yI)-[l) -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2>8-diazaspii,o[4.5]decane-3-cai,boxylic acid;
(S)-8-(2-amino-6-((R)-2}2,2-trifluoro- 1 -(3'-isopropyl-3-(3-methyl-l H-pyrazoi- 1 -yl)-[l, 1 '- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4,5]decane-3-cai'boxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluoiO-l-(3'-isopropoxy-3-(3-methyl-lH-pyrazol-l-yl)- [l} -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2J8-diazaspiiO[4.5]decane-3-cai'boxylic acid;
(S)-8-(2-amino-6-((R)-l -(4,-chloro-3,-methyl-3-(3-methyl-lH-pymzol-l-yl)-[l,r- biphenyl]-4-yl)-2,2;2-trifluoroethoxy)pyrimidin-4-yl)~2,8-diazaspiiO[4.5]decane-3-carboxyHc acid;
(S)-8-(2-amino-6-((R)-l-(3'-carbamoyl-3-(3-methyl-lH-pymzol-l-yl)-[l,l,-biphenyl]-4- yl)-2,2)2-trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-cai,boxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-tnfluoro-l ^
bis(trifluoiOmethy 1) 1 , Γ -biphenyl] - 4^
carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(3'-ethoxy-4'-fluoi -3-(3-methyl-lH-pyrazol-l-yl)-(;i ,l'- biphenyl]-4-yl)-2,2)2-tnfluoroethoxy)pyrimidin-4-yl)-2}8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)- 1 -(4'-chloro^
biphenyl]-4-yl)-2,2)2-trifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-H3\5'-dichloro^
yl)-2J2)2-tnfluoroethoxy)pyrimidin-4-yl)-2J8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)- 1 -(SHtert-butyO-S'-methyW-Q-methyl- 1 H-pyrazol- 1 -yl)-[l , 1 biphenyl]-4-yl)-2;2,2-ii'ifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)- 1 -(3'-chloi -3-(3-metliyl-lH-pyrazol- 1 -yl)-[i , 1 *-biphenyl]-4-yl)- 2,2,2-trifluoi ethoxy)pyi'imidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(3,-chloro-3-(3-methyl-lH-pyrazol-l-yl)-4'-(trifluoromethyl)- [l, -biphenyl]-4-yl)-2,2,2-trifluoiOethoxy)pyrimidin-4-yl)-2t8-diazaspiro[4,53decane--3- carboxylic acid;
(S)-8-(2-amino-6-((R)-2)2,2-trifl oi -l-(4'-methoxy-3-(3-methyl-lH-pyrazol-l-yl)-[lir- biplienyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chlolΌ-3 4,-dimethyl-[ls l,-bi he yl]-2-yl)-2ϊ2;2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspii [4,5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)- 1 -(5-chloiO-4'-eihoxy-3'-fluoro-[i , 1 '-biphenyl]-2-yl)-2,2,2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloiO-3, J5,-dimethyl-[l,l,-biphenyl]-2-yl)-2J2)2- trifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-cai'boxylic acid;
(S)-8-(2-amino-6-((R)-l 5-chloro-3'-methyl-4'-(trifluoiOmethoxy)-[ljr-biphenyl]-2-yl)- 2J2,2-ti'ifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4,,5-dichloiO-3',5,-dimethyl-[l)r-biphenyl]-2-yl)-2,2,2- trifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-l-(5-chloiO-4'-fluoiO-3,-methyl-[l)l'-biphenyl]-2-yl)-2;2J2- tiifluoi ethoxy)pyrimidin-4-yl)-258-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(3',5-dichloro-5'-methyl-[l,i'-biphenyl]-2-yl)-252)2- trifliioroethoxy)pyrimidin-4-yl)-2)8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloi -3,,4,,5'-trifluoi -[l ,l '-biphenyi]-2-yl)-2}2,2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloro-3H^^^
trifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloi -3, J5'-bis(trifluoi methyl)-[lil'-biphenyl]-2-yl)-2,2)2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloiO-3,-isopropyl-[l5l'-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2)2>2-trifluoi -l-(3',5,5,-trichloiO-[l5r-biphenyl]-2- yl)etlioxy)pyrimidm-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloro-4'-fluora-^^
2,2,2-tnfluoiOethoxy)pyriniidin-4-yl)-2,8-diazaspiiO[4.5Jdecane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloro-3'-fluoro-5,-isopropoxy-[l,r-biphenyl]-2-yl)-2)2i2- trifluoi ethoxy)pyiimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R 1 -(3'-(tert-butyl)-5-chloi -5'-methyl-[l , 1 '-biphenyl]-2-yl)-2s2,2- tnfluoiOeihoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloi -3,-fluoiO-4,-methyl-[l,l'-biphenyl]-2-yl)-2,2;2- ti'ifluoroethoxy)pyrimidin-4-yl)-2J8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-chloiO-2-(pyridin-3-yl)phenyl)-2,2,2- trifluoiOethoxy)pyrimidin-4-yl)-2>8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloro-3'-ethoxy-4,-fluoro-[ljr-biphenyl]-2-yl)-2)2}2" ti,ifluoiOethoxy)pyiimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-ethyl 8-(2-amiiio-6-((R)-l-(5-chlora-3, }4,-dimethyl-[l}l,-biphenyl]-2-yl)-2s2)2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4 5-dichloro-3',5,-dimethyl-[l)l'-biphenyl]-2-yl)-2,2J2- trifluoiOetlioxy)pyrimidin-4-y!)-2}8-diazaspiiO[4.5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-l -(5-chloro-4'-ethoxy-3'-fluoro-[l , I '-biphenyl]-2-yl)-2,2(2" tnfluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-ch oro-3 5^dimethyl-[lJΓ-biphe yl]-2-yl)-2J2)2·· ti'ifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(3'55-dichloro-5'-methyl-[lJl,-biphenyl]-2-yl)-2)2,2- trifluoi ethoxy)pynmidin-4-yl)-2,8-diazaspiro[4.53decane-3-carboxylate;
(S)-ethyl 8 2-amino-6 (R)-l-(5-chloro-4'-fluoro^^
tvifliioroethoxy)pyiimidin-4-yl)-2}8-diazaspiiO[4.5]decane-3-cai'boxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-3'-methyl-4'-(trifluoiOmethoxy)-[l,r-biphenyl]- 2-yl)-2,252-ti'ifluoroethoxy)pyrimidin--4-yl)-2)8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloiO-3*-(tnfliioi methoxy)-[l,r-biphenyl]-2-yl)- 2,2;2-trifliiOi ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloiO-3'-isopropyl-[ltl'-biphenyl]-2-yl)-2,2;2- trifluoroethoxy)pynmidin-4-yi)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloiO-3',5'-bis(trifluoromethyl)-[l5r-biphenyl]-2-yl)- 2J2J2-triflnoroethoxy)pyrimidin-4-yl)-2,8-diazaspii'o[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloi -3'-fluoi -4,-methyl-[l,r-biphenyl]-2-yl)-2,2,2- trifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2}2,2-tnfluoiO-l -(3^5)5 nchloiO-[l)l,-biphenyl]-2- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloiO-4'-fluoiO-3'-(trifluoi methyl)-[l ,l'-biphenyl]-2- yl)-2,252-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4-chloiO-2-(pyridin-3-yl)phenyl)-2,2,2- trifliioiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)- 1 5-chloro-3'-fluoro-5 sopropoxy-[l , 1 '-biphenyl]-2-yl)- 2,2,2 -ti'ifluoi ethoxy)pyrimidin-4-yl)-2}8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R> 1 -(5-chloiO-3'-ethoxy~5'-fluoi -[l ,1 '-biphenyl]-2-yl)-2,2,2- irifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-cai,boxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(3'-(tert-butyl)-5-chloiO-5'-meihyl-[l)l'-biphenyl]-2-yl)- 2,2,2-ti'ifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-(( )-l-(5-chloiO-3'-cyano-[l ,l!-biphenyl]-2-yl)-2,2,2- trifluoi ethoxy)pyrimidin-4-yl)-258-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl S^-amino-e-^-l-tS'-etho y-S'-fluoiO-S-fS-methyl-lH-p razol-l-yl)-!!,!'- biphenyl]-4-yl)-2,2J2-trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4,-chloro-3'-fluoi -3-(3-methyl-lH-pyrazol-l-yl)-[l ,l'- biphenyl]-4-yl)-2>2,2-trifliioroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l -(3,-chloi -4'-ethoxy-3-(3-methyi-lH-pyrazol- l-yl)-[i,l'- biphenyl]-4-yl)-2,2,2-tiifluoiOethoxy)pyrimidin-4-yl)-2)8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(3,-ethoxy-3-(3-methyl-lH-pyrazol-l-yl)-[l,l,-biphenyl]- 4-yl)-2,2,2-trifluoiOethoxy)pynmidin-4-yl)-2,8-diazaspiro[4,5]decane-3-cai'boxylate;
(S)-ethyl 8-(2-amino-6-(( )-l-(3',5,-difluolΌ-3-(3-metl yl-m-pyrazol-l-yl)-[l)l,- biphenyl]-4-yl)-252,2-tnfliioiOethoxy)pynmidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2)2-tnfluoi -l-(3-(3-methyl-lH-pyrazol-l-yl)-3'- (tnfl oiOmethyl)-[ljr-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloiO-3'-ethoxy-4,-fluoiO-[l,l,-biphenyl]-2-yl)-2,2,2- ti'ifliioiOethoxy)pyiimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-eihyl 8-(2-amino~6-((R)-2J2,2-trifluoiO-l-(3,-fluoiO-4'-isopi poxy-3-(3-methyl-lH- pyrazol- 1 -yl)-[l , 1 '-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3- carboxylate;
(S)-ethyl 8-(2-3ΐΏίηο-6-^)-1-(3';5'-^ηΐ6 1-3-(3-ιη6 1-1Η^ι¾ζο1-1^1)-[1,1'- biphenyl] -yl)-2,2,2-trifluoroethoxy)pyrimiditi-4-yl)-2,8-diazaspii [4.5]decane-3-caiboxylate;
(S)-ethyl 8-(2-aminO"6-((R)-l-(3,-chloiO-5'-methyl-3-(3-methyl-lH-pyrazol-l-yl)-[l,r- biphenyl] -yl)-2,2;2-ti fluoroethoxy)pyrimidin-4-yl)-2t8--diazaspiiO[4.5]decane-3-carboxylaie;
(S)-ethyl 8-(2-ammo-6-((R)-2,252-trifluoro- 1 3'-fluoro-4'-methyl-3-(3-methyl- 1 H- pyrazol- 1 -yl)-[l , 1 '-biplienyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(3*-(tert-butyl)-3-(3-methyl-lH-pyrazol-l-yl)-[lsl'- biphenyl]-4-yl)-2,2J2-ti fluoi ethoxy)pyrimidin-4-yl)-2J8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l -(3'-chloi -3-(3-methyl-lH-pyrazol-l-yl)-[l,l'-biphenyl]-4- yl)-2,2,2-ti,ifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate; (S)-ethyl
Figure imgf000452_0001
1 -yi)-[l , 1 '- biphenyl]-4-yl)-2J2)2-trifluoiOe†hoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethy 1 8-(2-amino-6-((R)- 1 -(3's4'-difluoi -3-(3-methyl- 1 H-pyrazol- 1 -y l)-[ 1 , 1 biphenyl]-4-yl)-2,2)2-trifluoiOethoxy)pyrimidin-4-yl)-2;8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2!2)2-trifl oiO-l-(4'-fluoiO-3-(3-methyl-ltI-pyrazol-l-yl)-3'- (trifluoiOmethyl)-[l, -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3- carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(3'-chloi -3-(3-methyl-lH-pyi-azol-l-yl)-5'- (trifluoiOmethyl)-[l, -biphenyl]-4-yl)-2,2,2-trifluoiOethoxy)pyrimidin-4-yl)-2;8- diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2t2,2-trifluoro-l -(3-(3-methyl-lH-pyrazol-l-yl)-3'- (ti fluoiOmethoxy)-[l5l'-biphenyl]-4-yl)eihoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(3,-(tert-buiyl)-5'-methyl-3-(3-methyl-lH-pyrazol-l-yl)- [l! -biphenyl]-4-yl)-252,2-trifluoi ethoxy)pyrimidin-4-yi)-2}8-diazaspii [4.5]decane-3- carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4'-chloiO-3'-methyl-3-(3-methyl-lH-pyrazol-l-yl)-[l>r- biphenyl] -yl)-2J2,2-trifluoToethoxy)pyiimidin-4-yl)-2J8-diazaspiiO[4.5]decane-3-cai'boxylate;
(S)-ethyl 8-(2-ammo-6-((R)-l-(4,-c oiO-3',5,-dimethyl-3-(3-methyl-lH-pyrazol-l-yl)- [l,r-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3- carboxylate;
(S)-ethyl 8-(2-amiiio-6-((R)-2,2,2~trifluoi - 1 -(4'-fluoro-3'-methyl-3-(3-methyl- 1H- pyrazol-l-yl)-[l,r-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3- carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4'-ethoxy-3'-fluoi -3-(3-methyl-lH-pyrazol-l-yl)-[l,l'- biphenyl]-4'yl)-2)2s2-trifluoiOethoxy)pynmidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(3^5,-dichloro-3-(3-methyl-lH-pyrazol-l-yl)-[l}r- biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidii -4-yl)-2J8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2J2-trifluoiO-l-(3,-isopropyI-3-(3-methyl-lH-pyrazol-l- yl)-[l , 1 ,-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2J8-diazaspiro[4.5]decane-3-carboxylate; (S)-ethyl 8-(2-3ΐηίηο-6-(( )-1-(4,-οΗ1οΐ -3-(3-ηΐ6 1-1Η^ϊΒΖο1-1^1)-3'- (trifluoiOmethyl)-[lJl'-biphenyl]-4-yl)-2,2,2-trifluoiOethoxy)pyrimidin-4-yl)-2J8- diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(3'-chloro-3-(3-methyl-lH-pyrazol-l-yl)-4'- (trifluorometliyl)-[lj -biphenyl]-4-yl)-2)2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l -(3'-carbamoyl-3-(3 -methyl- lH-pyrazol- 1 -yl)-[l , 1 '- biphenyl]-4-yl)-2J2,2-trifluoroethoxy)pyrimidin-4-yl)-2)8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2}2,2-trifluoro-i -(3-(3-methyl-lH-pyrazol-l-yl)-3l t5l- bis(trifluoromethyl)-[l, -biphenyl]-4-yl)ethoxy)pyiimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-252)2-trifluoiO-l-(3'-isopiOpoxy-3-(3-methyl-lH-pyiazol-i- yl)-[ljr-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2J8-diazaspii'o[4.5]decane-3-cai-boxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(3'-ethoxy-4*-fluoro-3-(3-methyI-lH-pyrazol-l-yl)-[l,r- biphenyl]-4-yl)-2,2,2-ti fluoiOethoxy)pyrimidin-4-yl)-2;8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2}2J2-trifluoiO-l-(3'-fluoro-5'-isopiOpoxy-3-(3-methyl-lH- pyrazol-i-yl)-[l, -biphenyI]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoiO-l -(4'-methoxy-3-(3-methyl-lH-pyrazol-l-yl)- [l, -biphenyl]-4-yl)ethoxy)pynmidin-4-yl)-2J8-diazaspiro[4,5]decane-3-carboxylate; and
(S)-ethyl 8-(2-amino-6-((R)-l -(4,-ethoxy-3-(3-methyl-lH-pyrazol-l-yl)-[l)l'-biphenyl]- 4-yl)-2,2,2-tnfluoroethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate;
or a pharmaceutically acceptable salt of any of the aforementioned.
123. The compound of claim 1 selected from:
(S)-8-(2-amino-6-((R)-l-(4,-etlioxy-3,-fluoiO-3-(3-methyl-lH-pyrazol-l-yl)-[l,r- biphenyl]-4-yl)-2J2,2-trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2)2,2 rifluoiO-l-(3,,4,,5'-trifluoi -3-(3-methyl-lH-pyrazol-l-yl)- [ljr-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R> 1 -(3'-chloi -4'-methyl-3 -(3-methyl- 1 H-pyrazol- 1 -yl)-[ 1 , Γ- biphenyl] -yl)-2,2J2-trifluoiOeihoxy)pyrimidin -yl)-2,8-diazaspiro[4.5]decane-3-cai'boxylic acid;
(S)-8-(2-amino-6-((R)-2,2)2-trifluoi -l -(3'-methyl-3-(3-methyl-lH-pyrazol-l-yl)-4'- (tnfluoiOmethoxy)-[l , -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-238-diazaspii [4.5]d
carboxylic acid;
(S)-8-(2-amino-6-((R)-2)252-trifluoi -l-(3'-fluoiO-5'-isopiOpoxy-3-(3-methyl-lH- pyrazoi- 1 -y])-[ 1 , 1 '-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspitO[4.5]decane-3- carboxylic acid;
(S)-8-(2-amino-6-((R 1 -(3'-chloro^
biphenyl]-4-yl)-2,2J2-tt,ifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)~ 1 -(4'-chloro-3 -(3 -methyl- 1 H-pyrazol-1 -yl)-3'-(trifluoiOmethyl)- [lj -biphenyl]-4-yl)-2,2,2-tnfluoi ethoxy)pyrimidin-4-yl)-2!8-diazaspiiO[4.5]decane-3- carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2J2-tnfluoi -l-(3'-fluo[ -3-(3-methyl-lH-pyrazol-l-yi)-5'- (tnfluoro]nethyl)-[l, -biphenyl]-4~yl)ethoxy)pyrimidin-4-y])-2)8-diazaspiro[4.5]decane-3- carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(3,-chloiO-4'-isopiOpoxy-3-(3-methyl-lH-pyrazol-l-yl)-[l,l'- biphenyl]-4-yl)-2,2J2-trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspii 4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-ti-ifluoiO-l-(2-(3-methyl-lH-pyrazol-l-yl)-4-(naphthalen-2- yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4,5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)- (4'-( enzyloxy)-3,-fluolΌ-3-(3-methyl-lH-pyl'azol-l -yl)-[l,l ,- biplienyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2;2-trifluoi -l-(4,-isopropoxy-3'-methyl-3-(3-methyl-lH- pyi,azol-l-yl)-[l)r-biphenyl]-4-yl)etlioxy)pynmidm-4-yl)-258-diazaspii'o[4,5]decane-3- carboxylic acid; (S)-8~(2-amino-6-((R)-2,2,2-trifluoro- 1 -(3'-fluoro-3-(3-methyl- 1 H-pyrazol- 1 -yl)-4'- propoxy-[l,l,-biphenyl]-4-yl)ethoxy)pyi'imidin-4-yl)-2J8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4'-butoxy-3'-fluoiO-3-(3-methyl-lH-pyrazol-l-yl
biphenyl]-4-yi)-2,2,2-ttifluoiOethoxy)pynmidiii-4-yl)-2}8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2J252-tnfluoro-l-(3,-fluoiO-4'-(5-methyl-l,3)4-oxadiazol-2-yl)-3- (3-methyl-lH-pyrazol-l-yl)-[l,r-biph.enyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2)2}2-trifluoiO-l-(3-(3-methyl-lH-pyrazol-l-yl)-4l- (methylsulfonyl)-[l, -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3- carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro- 1 -(3-(3-methyl- 1 H-pyrazol- 1 -yl)-4'-piOpoxy-[l , 1 '- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4,5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2)2-ti'ifluoro-l-(3-(3-methyl-lH-pyrazol-l-yl)-4,-((2~ morphol oethyl)carbamoyl)-[l , 1 ,-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4,5]decaiie-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro- 1 -(3-(3-methyl- lH-pyrazol- 1 -yl)-4'-sulfamoyl- [l( -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2)8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)- 1 -(4'-carbamoyl-3-(3-methyl - 1 H-pyrazol- 1 -yl)-[l , 1 '-biphenyl]-4- yl)-2J2>2-trifluoraethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluoiO-l-(3-(3-methyl-lH-pyrazol-l-yl)-4'- (methylcarbamoyl)-[l, -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2J8-diazaspiiO[4,5]decane-3- carboxylic acid;
(S)-8-(2-am o-6-((R)-2,2,2-trifluoro-l -(3'-fluoro-4'-me†hoxy-3-(3-methyl- 1 H-pyrazol-1 - yl)-[l , 1 '-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2J8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,252-trifluoiO- 1 -(3 -(3 -methyl- 1 H-pyrazol-1 -yl)-4'-(piperazine- 1 - carbony 1)- [ 1 , l'-bipheiiyl]-4-y l)ethoxy)pyrimidin-4-yl)-2, 8-diazaspiro [4.5]decane-3 -carboxylic acid; (S)-8-(2-amino-6-((R)-l-(4'-(dimethyicarbamoyl)-3-(3-methyl-lH-pyrazol-l-yl)-[i,l'- biphenyl]-4-yl)-2,2,2-trifliioi ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluoiO-i-(4'-isobutoxy-3-(3-methyl-lH-pyrazol-l-yl)- [1,1 '-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amillo-6-((R)-l-(4,-(diethylcal■bamo l)-3-(3-methyl-lH-p razol-l-yl)-[l}l,- biphenyl]-4-yl)-2,2,2-tiifliioi ethoxy)pyrimidin-4-yi)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2)2)2-trifluoiO- 1 -(3-(3-methyl- 1 H-pyrazol- 1 -yl)-4'- (neopentyloxy)-[l , -biphenyl]-4-yl)ethoxy)pyi'imidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid;
(S)-8-(2-amino-6-((R)-l -(4-(chroman-6-yl)-2-(3-methyl- lH-pyrazol- 1 -yl)phenyl)-2,2,2- trifluoi'oethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-(cinnolin-6-yl)-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2J2,2- irifluoi ethoxy)pyrimidin-4-yi)-2J8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2>2-trifluoiO-l-(3'-(hydroxymethyl)-4,-methyl-3-(3-methyl-lH- pyrazol-l-yl)-[l,r-biphenyi]-4-yl)ethoxy)pyiimidin-4~yl)-2,8-diazaspiro[4.5]decane-3- carbox lic acid;
(S)-8-(2-amino-6-((R)-252,2-tnfluoro-l-(4'-(hydiOxyiiiethyl)-3'-methyl-3-(3-methyl-lH- pyrazol-l-yl)-[l)l'-biphenyl]-4-yl)etlioxy)pyi"imidin-4-yl)-2J8-diazaspiro[4.5]decane-3- carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-(6-ethoxypyridin-3-yl)-2-(3~methyl-lH-pyiazol-l-yl)phenyl)- 2,2,2-trifluoi ethoxy)pyrimidin-4-yl)-2)8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((S)-l-(3',4'-bis(hydroxymethyl)-3-(3-methyl-lH-pymzol-l-yl)-[l,ll- biphenyl] -yl)-2)2J2-tiifluoroethoxy)pyi'imidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(3^4'-dime ^
biphenyl]-4-yl)-2,2,2-tnfluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decaiie-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-bromo-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2- trifIuoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-cai*boxylic acid; (S)-8-(2-amino-6-((R)- 1 -(4~chloiO-2-(3-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)phenyl)-2,2,2- ti'ifluoiOethoxy)pyrimidin-4-yl)-2}8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l -(2-(3-(tert-butyl)-lH-pyrazol-l-yl)-4-chloiOphenyi)-2,2,2- trifluoi ethoxy)pyt"imidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-chloiO-2-(3-isopropyl-lH-pyrazol-l-yl)phenyl)-2J2J2- trifluoiOethoxy)pyriniidin-4-yl)-2)8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-chloi -2-(3-cyclopropyl-lH-pyrazol- l-yl)phenyl)-2,2,2- trifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-tnfluoiO-l-(4'-(hydiOxymethyl)-4-(3-metriyl-lH-pyrazol-l- yl)-[l , 1 '-biphenyl]-3-yl)ethoxy)pyrimidin-4-yl)-258-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(3'-(teit-butyl)-5-chloi -[l ,l,-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloro-3'-(prop-l-en-2-yl)-[l !l '-biphenylJ-2-yl)-212,2- tiifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-caiboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-chloi -2-(2-(dimethylamino)pyridin-4-yl)phenyl)-2,2,2- trifIuoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-chloiO-2-(naplithalen-2-yl)phenyl)-2}2,2- trifluoiOethoxy)pyrimidiii-4-yl)-2!8-diazaspitO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-chloi -2-(2-isopropylpyridin-4-yl)phenyl)-252,2- trifluoroethoxy)pyrimidin-4-yl)-2 ,8-diazaspiro [4.5] decane-3 -carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloi -4'-fluoi -[lJl'-biphenyl]-2-yl)-2,2,2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4',5-dichloiO-i;i ,r-biplienyl]-2-yl)-2,2J2- trifluoroethoxy)pyrimidin-4-yl)-2)8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloro-4'-methyl-[l,l '-biphenyI]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-cai'boxylic acid;
(S)-8-(2-amino-6-((R)- 1 -(5-chloiO-2,,3',4',5,-tetrahydiO-[l , 1 ,-biphenyl]-2-yl)-2>2,2- tiifluoiOethoxy)pyrimidin-4-yl)-218-diazaspiiO[4,5]decane-3-caiboxylic acid;
(S)-8-(2-amino-6-((R)- 1 -(5-chloro-3'-isobutoxy-[ 1 , 1 '-biphenyl]-2-yl)-2,2,2- trifliioroethoxy)pyrimidin-4-yl)-2>8-diazaspiiO[4,5]decane-3~cai'boxylic acid; (S)-8-(2-amino-6-((R)-l -(5-chloi -3'-(pynOlidine-l-carbonyl)-[l,l,-biphenyl]-2-yl)- 2,2,2-trifluoroeihoxy)pynmidiii-4-yl)-2,8-diazaspiro[4.5]decane-3-cai,boxylic acid;
(S)-8-(2-amino-6-((R)-l -(5-chloi -3'-(cyclopentyloxy)-[l Jl'-biplienyl]-2-yl)-2,2;2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloiO-3,-(((lR,4R)-4-hydiOxycyclohexyl)carbamoyl)-[l 5l'- bipheiiyl]-2-yl)-2;2J2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloiO-3'-ethyl-[l,r-biphenyl]-2-yl)-2,2,2- trifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspii'o[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloiO-3'-isopropyl-[l}l'-biphenyl]-2-yl)-2)252- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R) -(5-c loiO-3H^
bip enyl]-2-yl)-2,2}2-trifliioroethoxy)pyrimidin-4-yl)-2;8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloiO-3'-(morpholine-4-carbonyl)-[l,l'-biphenyi]-2-yl)- 2,2,2-trifluoi ethoxy)pynmidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l -(5-chloro-3'-(4-methylpiperazine- 1 -carbonyl)-[l , T-biphenyl]-2- yl)-2,2)2-trifluoroethoxy)pyrin'iidin-4-yl)-2,8-diazaspiiO[4.5]decane--3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-chloiO-2-(2-methylthiazol-5-yl)phenyl)-2,2}2- trifluoroethoxy)pyi'imidin-4-y])-2,8-diazaspiiO[4,5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-chloi -2-(l-methyl-2-oxo-l ,2-dihydi pyridin-3-yl)phenyl)- 2J2,2-ti'ifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l -(5-chloi -3'-(N-methylsuIfamoyl)-[l,r-biphenyl]-2-yl)-2,2,2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4,5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloiO-3,-(NJN-dimethylsulfamoyl)-[l,r-biphenyl]-2-yl)- 2,2,2-trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-caiboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloiO-3,-(methylcarbamoyl)-[l,l'-biphenyl]-2-yl)-2,2,2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloro-3,-(dimethylcarbamoyl)-[lfl'-biphenyi]-2-yl)-2,2,2- tnfluoi'oethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)- 1 -(5-chloro-3'-(diethylcarbamoyl)-[l , l'-biphenyl]-2-yl)-2,2,2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(6-((R)-l-(2-(lH-benzo[d]imidazol-4-yl)-4-chloiOphenyl)-2,2)2-trifluoroetlioxy)-2- aminopyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloiO-3'-(piperazine-l-carbonyl)-[l,l'-biphenyl]-2-yl)-2!2,2- tnfluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(5-chloi -3'-(4-cyclopropylpiperazine-l-carbonyl)-[l,r- biphenyl]-2-yl)-2,252-tnfluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4~chloiO-2-(pyridin-2-yl)phenyl)-2}2,2- trifluoiOethoxy)pyi'imidin-4-yl)-2!8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-chloro-2-(pyrimidin-2-yl)phenyl)-2}2,2- tiifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-chloro-2-(pyrazin-2-yl)phenyl)-2(2,2- tnfl oroethoxy)pyi-imidin-4-yl)-2J8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l -(5-chloro-3'-(2-methoxyethoxy)-[l , 1 '-bi henylj^-yl)^^^- tnfluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(6-((R)- 1 -(2-(l H-benzo[djimidazol-i -yl)-4-chloiOp enyl)-2,2,2-trifluoi ethoxy)-2- aminopyrimidin-4-yl)-2;8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)- 1 -(4-chlora-2-(l H-indazol- 1 -yl)phenyl)-2,2,2- trifluoi'oethoxy)pyi,imidin~4-yl)-2,8-diazaspiro[4.5]decane-3-cai,boxylic acid;
(S)-8-(2-amino-6-((R)- 1 -(4-bromo-2-(piperazin- 1 -yl)phenyl)-2,2,2- trifluoiOetlioxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluoiO-l-(4,-isopropoxy-3-(piperazin-l-yl)-[l ,i'-biphenyi]- 4-yi)ethoxy)pyrimidin-4-yl)-2,8-diazaspii'o[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2!2-trifluoiO- 1 -(4'-isopropoxy-3-morpholino-[l ,1 '-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(6-((R)-l-([l,l,-bipl enyl]-2-yI)-2,2,2-trifluoi ethoxy)-2-amino pyrimidin-4-yl)- 2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2)2,2-trifluoro- 1 -(4-isopropoxy-[l , 1 ':3', 1 "-teiphenyl]-4'- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4,5]decane-3-carboxylic acid; (S)-8-(2-amino-6-((R)-252)2-trifluoiO-l-(4-piOpoxy-[lJl,:3 lM-terpheny
yl)ethoxy)pyMmidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluoro - 1 -(5-(methylsulfonyl)-[ 1 , 1 '-biphenyl]-2- yl)ethoxy)pyijmidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-ammo-6-((R)-2,2,2-trifluoi ^^
yl)ethoxy)pyrimidin~4-yi)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(3,4-dimethyl-[l,l ':3,,l"-terpheiiyl]-4,-yl)-2;2}2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(6-((R)- 1 -([1 , Γ:3', I M-teiphenyl3-4'-yl)-2J2J2-tnfluoroethoxy)-2-aminopyrimidin-4- yl)-258-diazaspiio[4.5]decane-3-carboxylic acid;
(R)-8-(2-amino-6-((R)- 1 -(5-chloro-[l , 1 ,-biphenyl]-2-yl)-2,2)2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(R)-8-(2~amino-6-((S)-l -(5-chloro-[l ,1 ,-biphenyl]-2-yl)-2,2J2-trifluoroethoxy)pyrimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((S)- 1 -(5-chloro-[l , 1 '-biphenyl]-2-yl)-2)2,2-trifluoroethoxy)pyrimidin- 4-yl)-2;8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)~8-(2-amino-6-((S)-l-(3\4'-dimetl^
yl)-2J2,2-tnfluoiOetlioxy)pyi'imidin-4-yl)-2J8-diazaspii'o[4.5]decane-3-cai'boxylic acid;
(R)-8-(2-amino-6-((S)-l~^4'-dim^
yl)-2,2,2-trifluoroe†hoxy)pyrimidin-4-yl)-2s8-diazaspiiO[4.5]decane-3-carboxylic acid;
(R)-8-(2-amino-6-((R)-l-(3's4,-dimethyl-3-(3~methyl-lH-pyrazol-l-yl)-[l3l'-biphenyl]-4- yl)-2J2,2-trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluoiO-l-(4-(3-fluoiOquinolin-6- yl)phenyl)ethoxy)pyrimidin-4-yl)-2)8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-trifluoiO-l-(4'-propoxy-[ljr-biphenyl]-4- yl)ethoxy)pyt'imidin-4-yl)-2}8-diazaspiiO[4.5]decane-3-cai'boxylic acid;
(S)-8-(2-amino-6-((R)-l-(4,-(diethylcarbamoyl)-[l,l '-biphenyl]-4-yl)-2)2,2- trifluoroethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4,5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4,-carbamoyl-[l}l,-biphenyl]-4-yl)-2,2,2- trifluoiOethoxy)pyrimidin-4-yl)-2)8-diazaspii [4.5]decane-3-cai-boxylic acid; (S)-8-(2-amino-6-((R)-2,2,2-trifluoro - 1 - (4'-(methylcarbamoyl)-[ 1 , 1 '-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-araino-6-((R)-2,2,2-trifluoro-l -(4'-((2-moipholinoethyl)carbamoyl)-[l , 1'- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2J2,2-trifluoi -l-(4'-(methylsuifonyl)-[l}r-biphenyl]-4- yl)ethoxy)pynmidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2!2-trifluoiO-l-(4'-sulfamoyl-[l ,l'-biphenyl]-4- yl)ethoxy)pyi,imidin-4-yl)-2)8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4'-(diniethylcarbamoyl)-[l ,l'-biphenyl]-4-yl)-2J2)2- trif uoroettioxy)pyrimidin-4-yl)-2J8-diazaspiiO[4,5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-tnfliioi -l-(4,-(piperazine-l-cai onyl)-[l,r
yl)ethoxy)pyriraidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2,2,2-tiifliioi -l -(3'-fluoi -4'-piOpoxy-[l,l l-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4,5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l -(4,-etlioxy-3'-iliioiO-[l)l'-biphenyl]-4-yl)-2}2)2- tiifIuoioethoxy)pynmidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-caiboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4'-ethoxy-[l)l,-biphenyl]-4-yl)-2)2,2-tnfluoi ethoxy)pytimidin- 4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-(cinnolin-6-yl)phenyl)-2,2>2-trifluoi'oethoxy )pyrimidin-4- yl)-258-diazaspii [4.5]decane-3-cai'boxylic acid;
(S)-8-(2-amino-6-((R)-l-(4-(chroman-6-yl)phenyl)-2,252-trifluoi ethoxy)pyrimidin-4-yl)- 2>8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-2J2,2-trifluoro-l-(4-(3-fluoroqiunolin-6-yl)-2- methylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid;
(S)-8-(2-amino-6-((R)-l-(2-ethyl-4-(3-fluoi qiunolin-6-yl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylic acid;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro- 1 -(3',4',5'-trifluoro-3-(3-methyl- 1 H-pyrazol- l-yl)-[l, -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2f8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-1 -(4-chloro-2-(l -methyl -2-oxo-l, 2-dihydropyridin-4- yl)phenyl)-2,2,2-trifluoiOethoxy)pyrimidin-4-yI)-258-diazaspii-o[4.5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2)2-trifluoiO-l-(3,-methyl-3-(3-methyl-lH-pyrazol-l-yl)- 4'- (trifluoromethoxy) - [ 1 , 1 '-bipheny l]-4-yl) ethoxy)pyrim id i n-4-yl)-2 , 8 - di azaspiro [4 ,5]decane-3- carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(3^chloiO-4'-methyl-3-(3-methyl-lH-pyrazol-l-yl)-[l ,l'- biphenyl]-4-yl)-2,2J2-trifluoroethoxy) pyrimidin-4-yl)-258-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-aniino-6-((R)-2,2;2-trifluoi -l-(3'-fluoi -3-(3-methyl-lH-pyrazol-l-yl)-5'-
Figure imgf000462_0001
,r-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate;
(S)-ethyl 8-(2-amino-6 (R)-l-(3'-chloiO-5'-fluoiO-3-(3-methyl-lH-pyrazol-l-yl)-[l,l '- biphenyl]-4-yl)-2,2,2-ti,ifluoroethoxy)pyrimidin-4-yl)-258-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloi -3'-cyclopi pyl-[l,l,-biphenyl]-2-yl)-2,2;2- trifluoi ethoxy)pyrimidin-4-yl)-2,8-diazasp O[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(3'-chloro-4'-isopi poxy-3-(3-niethyl-lH-pyrazol-l-yl)- [1,1 '-biphenyl]-4-yl)-2,2,2-trifluoiOethoxy) pyrimidin-4-yl)-2,8-diazaspiiO[4,5]decane-3- carboxylate;
(S)-ethyl 8-(2-amino-6-((R)- 1 -(2-(benzo[d]thiazol-5-yl)-4-chloiOphenyl)-2,2s2- tfifliioi ethoxy)pyrimidin-4-yl)-2;8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R 1 -(4-chloiO-2-(2-(dimethylamino)pyridin-4-yl)phenyl)-2,2,2- trifluoi ethoxy)pyiimidin-4-yI)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4-chloiO-2-(naphthaien-2-yl)phenyl)-2,2,2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyI 8-(2-amino-6-((R)-l-(3,-(tert-butyl)-5-chloiO-[l,r-biplienyl]-2-y
trifluoiOethoxy)pyi'imidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(6-((R)-l-(2-(lH-benzo[d]imidazol-l-yl)-4-chlorophenyl)-2,2,2- trifluoi ethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)- 1 -(4-chloro-2-(l H-itidazol- 1 -yl)pheny l)-2,2,2- trifluoroethoxy)pynmidin-4-yl)-2;8-diazaspii'o[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4-cliloi -2-(2-isopiOpylpyridin-4-yl)phenyl)-2,2,2- ti'ifluoiOethoxy)pyrin idin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloiO-4,-fluoi -[l jr-biphenyl]-2-yl)-2!2,2- trifluoroethoxy)pyrimidin-4-yl)-2J8-diazaspiiO[4.5]decane-3-carboxylate; (S)-ethyl S^-amino-e-^-i ^'^-dichloiO-tl '-biphen ll^-yl)^^^- ti'ifluoiOethoxy)pyriniidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-cai'boxylate;
(S)-ethyl 8-(2-amino-6-((R)-l -(5-chloi "4'-methyl-[l,r-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pynmidin-4-yl)-2}8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro- 1 -(2-(3 -methyl- 1 H-pyrazol- 1 -yl)-4- (naphthalen-2-yl)phenyl)ethoxy)pyrimidin-4-yl)-2>8-diazaspiro[4,5]decane-3-carboxyiate;
(S)-ethyl 8-(2-amino-6-((R)-l -(S-chloro^'^'^'^'-tetiahydro-tl ,1 ,-biphenyl]-2-yl)-2J2;2- trifluoiOetl oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)- 1 -(4'-(benzyloxy)-3'-fluoro-3-(3-methyl-l H-pyrazol- 1 -yl)- [l,r-biphenyl]-4-yl)-2,2,2-trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4,5]decane-3- carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoiO-l-(4'-isopiOpoxy-3'-methyl-3-(3-methyl-lH- pyrazol-l -yl)-[l,r-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspii'o[4.5]decane-3- carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l -(5-chloi -3'-isobutoxy-[l)l,-biphenyl]-2~y!)-2)2,2- tnfluoiOethoxy)pyrimidin-4-yl)-2s8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2;2-trifluoiO-l -(4-isopropoxy-[l ,l':3,,l"-terphenyl]-4'- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylaie;
(S)-ethyl 8-(2-amino-6-((R)-2,2)2-trifluoiO-l-(4-(3-fluoroqimiolin-6- yl)phenyl)ethoxy)pyi'imidin-4-yl)-258-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2;2-tnfluoiO-l -(3,-fliioi -3-(3-niethyl-lH-pyrazol-l-yl)-4'- pi poxy-[l3 -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4,-butoxy-3,-fluoro-3-(3-methyl-lH-pyrazol-l-yl)-[lJl'- bipbenyl]-4-yl)-2,252-trifluoiOethoxy)pyrimidin-4-yl)-2}8-diazaspiiO[4.5]decane-3-carboxylaie;
(S)-ethyl 8-(2-amino-6-((R)-2,2}2-trifluoiO-l-(3'-fluoiO-4'-(5-meihyl-l}354-oxadiazol-2- yl)-3-(3-methyl-lH-pyrazol-l-yl)-[l,r-biphenyl]-4-yl)ethoxy)pyi'imidin-4-yl)-2,8- diazaspi ro [4.5] decane- 3 - carboxy late;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloi -3'-(pynOlidine-l-carbonyl)-[l )l'-biphenyl]-2- yl)-2,232-tnfluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloiO-3'-(cyclopentyloxy)-[l,r-biphenyl]-2-yl)-2t2!2- tiifluoroethoxy)pyrimidin-4-yl)-2}8-diazaspii [4.5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloi -3'-(morpholine-4-carbonyl)-[l,r-biphenyl]-2- yl)-2,2,2-ti,ifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloi -3*-(((lR,4R)-4-hydiOxycyclohexyl)carbamoyl)- [l, -biphenyl]-2-yl)-2,252-ttifliioroethoxy)pyriniidin-4-yl)-2,8-diazaspiiO[4.5]decane-3- carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-3,-ethyl-[l,l,-biphenyl3-2-yl)-2,2,2- trifluoiOetlioxy)pyrimidin-4-yl)-2,8-diazaspii'o[4.5]decane-3-cai'boxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloiO-3'-isopiOpyl-[l ,l'-biphenyl]-2-yl)-2,2)2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-cai*boxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-tvifluoro-l -(4'-propoxy-[l ,1 '-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(2-ethyl-4-(3-fluoi quinolin-6-yl)phenyl)-2,2;2- trifluoiOethoxy)pyrimidiii-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l -(5-chloro-3,-(4-methylpiperazine- 1 -carbonyl)-[l, 1'- biphenyl]-2-yl)-2,2>2-trifluoiOethoxy) pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2>2-tnfluoro- ί -(4-(3-fiuoroquinolin-6-yl)-2- metliylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)"l-(4,-(diethylcarbamoyi)-[l ,l,-biphenyl]-4-yl)-2,2,2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4'-carbamoyl-[l ,l'-biphenyl]-4-yl)-2,2}2- trifl oiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4,5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)- 1 -(4-chloiO-2-(2-methylthiazol-5-yl)phe yl)-2)2,2- trifluoroethoxy)pyrimidtn-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-aminO"6-((R)-2)2,2-trifluoiO-l-(4-pi poxy-[l ,l,:3',r,-terphenyl]-4'- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4-chloro-2-(5-chlorothiophen-2-yl)phenyl)-2,2)2- tiifluoiOethoxy)pyrimidin-4-yl)-2;8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoiO- 1 -(4'-(methylsulfonyl)-[l , 1 '-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4,5]decane-3-carboxylate; (Syethyl 8-(2-amino-6-((R)-2,2,2-trifluoro- 1 -(3-(3-methyl- 1 H-pyrazol- 1 -yl)-4'- (methylsulfonyl)-[l,r-biphenyl]-4-yl)ethoxy)pynmidin-4-yi)-2,8-diazaspiiO[4.5]decane-3- carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2;2,2-trifluoro-l-(3-(3-methyl-lH-pyrazol-l-yl)-4'-piOpoxy- [1 ,1 ,-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2J8-diazaspiiO[4.5]decane-3-carboxy!ate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4'-(diethylcarbamoyl)-3-(3-methyl-lH-pyrazol-l-yl)- [l, -biphenyl]-4-yl)-2,2,2-trifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3- carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2}2-trifluoi -l -(4'-(methylcarbamoyl)-[ , 1 '-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-258-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoiO-l-(3-(3-methyl-l H-pyrazol- l-yl)-4'- sulfamoyl-[l,r-bipheiiyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-cai'boxylate;
(S)-ethyl 8-(2-amino-6-((R)-2;2)2-trifluoro-l-(4,-sulfamoyl-[l,l'-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoi -l -(4'-((2-morpholinoethyl)carbamoyl)-n , 1 '- biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4,5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-l -(3-(3-methyl-l H-pyrazol- l-yl)-4'-((2- morpholinoethyl)carbamoyl)-[l , 1 ,-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4^(dimeibylcai amoyl)-[l,r-biphenyl]-4-yl)-2,2^ trifluoiOethoxy)pyrimidin-4--yl)-2,8-djazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2}2,2-trifluoiO- 1 -(4'-(piperazine- 1 -carbonyl)-[l , 1 '-biphenyl]- 4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoi -l-(3-(3-methyl-lH-pyrazol-l-yl)-4'- (piperazine-l-carbonyl)-[l, -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2J8-diazaspii [4.5]decane- 3 -carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-i-(4-chloiO-2-(l-methyl-2-oxo-l ;2-dihydiOpyndin-3- yl)phenyl)-2,2,2-trifluoiOeihoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4,-(dimethylcarbamoyl)-3-(3-methyl-lH-pyrazol-l-yl)- [1 , 1 ,-biphenyl]-4~yl)-2,2;2-tnfliioiOethoxy)pyrirnidin-4-yl)-2,8-diazaspii [4.5]decane-3- carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,2J2-trifluoi -l-(3'-fluoiO-4'-methoxy-3-(3-methyl-lH- pyrazol- l -yl)-[l ,l '-biphenyl]-4-yl)ethoxy)pyrimidm-4-yl)-2,8-diazaspii [4.5]decane-3- carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoi -l-(3'-fluoiO-4'-piOpoxy-[l}r-biphenyl]-4- yl)ethoxy)pyrimidin-4-yl)-2}8-diazaspii [4.5]decane-3-carboxylate;
(S)-ethyl 8-(2^ϊηο-6-((Κ)-2,2,2 πί1υοΓθ-1-(3-(3-ηιε 1-1Η^Γαζοί-ί -> )-4*- (methylcarbamoyl)-[l, -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3- carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l -(5-chloro-3'-(N-methylsulfamoyl)-[l,l'-biphenyi]-2-yl)- 2,2,2-trifl oiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloiO-3'-(N,N-dimethylsulfamoyl)-[l,l '-biphenyl]-2- yl)-2,2,2-trifluoi ethoxy)pyiimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2J2-trifluoiO-l-(4'-isopi poxy-3-moipholino-[l, - biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2J8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)- 1 -(5-chloro-3'-(methylcarbamoyl)-[l , 1 '-biphenyl]-2-yl)- 2,2,2-trifluoi ethoxy)pyiimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloiO-3'-(dimethylcarbamoyl)-[l> -biphenyl]-2-yl)- 2,2,2-trifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiio[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l -(4'-etlioxy-3'-fluoiO-[l>r-biphenyl]-4-yl)-2,2)2- tnfluoroethoxy)pyrimidin-4-yl)-2J8-diazaspiro[4,5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)- l-(4'-ethoxy-[l,r-biphenyl]-4-yl)-2,2,2- trifluoi ethoxy)pynmidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-252)2-ti'ifluoro-l-(5-(meihylsulfonyl)-[l,r-biphenyl]-2- yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.53decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R) -(5-chloro-3'-(diethylcarbamoyl)-[l,r-biphenyl]-2-yl)- 2,2,2-tnfluoroethoxy)pyrimidm-4-yl)-2,8-diazaspiiO[4.5]decane-3-caiboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2}2-trifluoro-l -(4'-isobutoxy-3-(3-methyl- lH-pyrazoi-1 - yl)-[l, -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2)8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifliioiO- 1 -(3-(3-methyl-lH-pyrazol-l -yl)-4'- (neopeniyloxy)-[l,r-biplienyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate; (S)-ethyl 8-(6-((R)-l-(2-(lH-benzo[d]imidazol-4-yl)-4-chlorophenyl)-2,2J2- ti,ifliioiOethoxy)-2-aminopyrimidin-4-yl)-2t8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4-(chiOman-6-yl)-2-(3-methyl-lH-pyrazol-l -yl)phenyl)- 2,2,2 nfluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloiO-3'-(piperazme-l-carbonyl)-[l ,l'-biphenyl]-2-yl)- 2,2,2-trifluoi ethoxy)pyrimidin-4-yl)-2J8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloi -3'-(4-cyclopropylpiperazine-l-cai'bonyl)-[l,r- biphenyI]-2-yl)-2,2,2-trii ioroethoxy) pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)~ethyl 8-(2-amino-6-((R)- 1 -(4-(cinnolin-6-yl)-2-(3-methyl- lH-pyrazol- 1 -yl)phenyl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2}8-diazaspiro[4.53decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)- 1 -(4-chloro-2-(3-(trifluorometliyl)- 1 H-pyrazol- 1 -yl)phenyl)- 2,2,2-ti'ifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(2-(3-(tert-butyl)-lH-pyrazol"l-yl)-4-chloiOphenyl)-2)2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l -(4-chloro-2-(3-isopropyl-l H-pyrazol- l-yl)phenyl) -2,2,2- trifliioiOethoxy)pyi'imidin-4-yl)-2,8-diazaspiro[4.5]decane-3-caiboxylate;
(S)-ethyl 8-(2-amino-6-((R)- 1 -(4-cliloro-2-(3-cyclopropyl- 1 H-pyrazol-1 -yl)phenyl)- 2 ,2,2 -trifliioro ethoxy)pyrimidi n-4 -y 1) -2, 8 -diazaspiro [4.5] decane-3 - carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(3')4'-dimethyi-3-(3-(trifluoi methyl)-lH-pyrazol-l-yl)- [l, -biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5]decane-3- carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l -(3i4-dimethyl-[l,l':3,,l"-terphenyl]-4'-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2, 8 -diazaspiro [4.5]decane-3 -carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2;2,2-tnfluoi -l-(3-fluoiO-4-pi poxy-[l ,l ,:3'!l"-terphenyl]- 4'-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(6-((R)-l-([l;r-biphenyl]-2-yl)-2J2,2-trifluoroethoxy)-2-aminopyrimidin-4- yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(6-((R)-l-([l51^3^ '*-te^
aminopyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate; (S)-ethyl 8-(2-amino-6-((R)-2,252-trifluoi -l-(4'-(hydiOxymethyl)-4-(3-methyl-lH- pyrazol-l-yl)-[l,l'-biphenyl]-3-yl)ethoxy) pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- caiboxylate;
(S)-ethyl 8-(2-amino-6-(( )-l-(4-(cliroman-6-yl)phenyl)-2,2,2-ti'ifluoroethoxy)pyrimidin- 4-yl)-2}8-diazaspiio[4.5]decane-3-cai'boxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4-chloiO-2-(pyridin-2-yl)phenyl)-252,2- tnfluoiOethoxy)pynmidin-4-yl)-2J8-diazaspiro[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4-chloi -2-(pyrimidin-2-yl)phenyl)-2J2i2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2;2,2-trifluoro-l -(3'-(hydiOxymethyl)-4'-methyl-3-(3-methyl- lH-pyrazol-l-yl)-[l,l'-biphenyl]-4-yl)ethoxy)pynmidin-4-yl)-2,8-diazaspiiO[4.5]decane-3- carboxylate;
(S)-ethyI 8-(2-amino~6-((R)-2,2J2-triaioi -l-(4'-(hydi xymethyl)-3'-methyl-3-(3-methyl- lH-pyrazoI- 1 -yl)-[l , 1 '-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2;8-diazaspiro[4.5]decane-3- carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l -(4-(6-ethoxypyridin-3-yl)-2-(3-methyl-lH-pyrazol-l- yl)phenyl)-2,2,2-trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-caiboxylate;
(S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoi -l-(4-(6-methoxypyridin-3-yl)-2-(3-methyl- 1 H-pyrazol- 1 -yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-3,-(2-methoxyeihoxy)-[l ,l'-biphenyl]-2-yl)- 2,2,2-trifluoi ethoxy)pyrimidin-4-yl)-2;8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((R)-l-(4-ch]oiO-2-(pyrazin-2-yl)phenyl)-2,2,2- ti'ifliioiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-ethyl 8-(2-amino-6-((S)-l-(3,,4'-bis(liydi xymethyl)-3-(3-methyl-lH-pyrazol-l-yl)- [l}r-biphenyl]-4-yl)-2,2,2-trifluoi ethoxy)pyrirnidin-4-yl)-2,8-diazaspiiO[4.5]decane-3- carboxylate;
(S)-tert-butyl 8-(2-amino-6-((R)-l-(3,,4,-dimethyl-3-(3-methyl-l H-pyrazol- l-yl)-[l ,T- biplienyl]^-yl)-2,2,2-triflxiOi ethoxy)pyrimidin-4-yl)-258-diazaspiiO[4.5]decane-3-carboxylate;
(S)-tert-butyl 8"(2-amino-6-((R)-2,252-trifluoiO-l-(4,-isopropoxy-3-(3-methyl-lH- pyrazol-l-yl)-[l, -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3- carboxylate; (S)-isopropy 1 8-(2-amino-6-((R)- 1 -(3',4'-dimethyl-3-(3-methyl- 1 H-pyrazol - 1 -yl)-[ 1 , 1 '- biphenyl]-4-yl)-2,2;2-tiifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-cai'boxylate;
(S)-cyclopentyl 8-(2-amino-6-((R)-l-(3')4,-dimeihyl-3-(3-methyl-lH-pyrazol-l-yi)-[ljr- biphenyl]-4-yl)-2J2,2-tiifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspii [4.5] decane-3-carboxylate;
(S)-methyl 8-(2-amino-6-((R)-l-(3'J4'-dimethyl-3-(3-methyl-lH-pyrazol-l-yl)-[l)l*- bipheny!]-4-yl)-2}2,2-trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4,5] decane-3-carboxylate;
(S)-plΌpyl 8-(2-amino-6-((R)-l-(3 4,-dimethyl-3-(3-methyl-lH-pyl·azol-l-yl)-[l,l,- biphenyl]-4-yl)-2,2,2-trifliioroethoxy)pyrimidin-4-yl)-2}8-diazasphO[4.5] decane-3-carboxylate;
(S)-isopropyl 8-(2-amino-6-((R)-2,2)2-tiifliioiO-l-(4'-isopropoxy-3-(3-methyl-lH- pyrazol-l -yl)-[l, -biphenyl]-4-yl)ethoxy)pyi'imidin-4-yl)-2,8-diazaspii [4.5]decane-3- carboxylate;
(S)-cyclopentyl 8-(2-amino-6-((R)-2)2,2-trifluoro-l-(4,-isopropoxy-3-(3-methyl-lH- pyrazol- 1 -yl)-[l , -biphenyl]-4-yl)ethoxy)pynmidin-4-yl)-2,8-diazaspiro [4.5]decane-3- carboxylate;
(S)-propyl 8-(2-amino-6-((R)-2,2,2-trifluoro- 1 -(4'-isopiOpoxy-3-(3-methyl- lH-pyrazol- 1 - yl)-[l, -biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro [4.5]decaiie-3-carboxylate;
(S)-isopropyl 8-(2-amino-6-((R)-l-(5-chloro-[l;l'-biphenyI]-2-yl)-2,2J2- trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4,5]decane-3-carboxylate;
(S)-cyclopentyl 8-(2-amino-6-((R)-l-(4,-chloi -3-(3-methyl-lH-pyrazol-l-yl)-[l5l'- biphenyl]-4-yl)-2J2,2-tnfluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4.5]decane-3-carboxylate;
(S)-propyl 8-(2-amino-6-((R)- 1 -(5-chloro-[ 1 , 1 '-biphenyl]-2-yl)-2,2J2- trifl oroethoxy)pyrimidin-4-yl)-2}8-diazaspiiO[4.5]decane-3-carboxyiate;
(S)-methyl 8-(2-amino-6-((R)-l-(5-chloiO-3'-(methylsulfonyl)-[l)l'-biphenyl]-2-yl)- 2,2,2-trifluoiOethoxy)pyrimidin-4-yl)-2,8-diazaspiiO[4,5]decane-3-carboxylate; and
(S)-methyl 8-(2-amino-6-((R)-l-(5-chloiO-3,-sulfamoyl-[l,r-biphenyl]-2-yl)-2,2,2- trifluoi ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate;
or a pharmaceutically acceptable salt of any of the aforementioned.
124. A pharmaceutical composition comprising a compound of any one of claims 1-123, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
125. A method of inhibiting TPH1 comprising contacting said TPH1 with a compound of any one of claims 1-123, or a pharmaceutically acceptable salt thereof.
126. A method of lowering peripheral serotonin in a patient comprising administering to said patient a compound of any one of claims 1-123, or a pharmaceutically acceptable salt thereof.
127. A method of treating or preventing a disease in a patient, wherein said disease is selected from bone disease, cardiovascular disease, metabolic disease, pulmonary disease, gastrointestinal disease, liver disease, cancer, and inflammatory disease, comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1-123, or a
pharmaceutically acceptable salt thereof. 28. The method of claim 127 wherein said bone disease is osteoporosis, osteoporosis pseudoglioma syndrome (OPPG), osteopenia, osteomalacia, renal osteodystrophy, Paget's disease, bone fracture, and bone metastasis.
129. The method of claim 128 wherein said osteoporosis is primary type 1 osteoporosis.
130. The method of claim 127 wherein said cardiovascular disease is pulmonary arterial hypertension (PAH).
13 . The method of claim 130 wherein said PAH is associated pulmonary arterial
hypertension (APAH).
132. The method of claim 127 wherein said metabolic disease is diabetes or hyperlipidemia.
133. The method of claim 127 wherein said pulmonary disease is chronic obstructive pulmonary disease (COPD) or pulmonary embolism.
134. The method of claim 127 wherein said gastrointestinal disease is irritable bowel disease (IBD), colitis, chemotherapy-induced emesis, diarrhea, carcinoid syndrome, celiac disease, Crohn's disease, abdominal pain, dyspepsia, constipation, lactose intolerance, MEN types I and II, Ogilvie's syndrome, pancreatic cholera syndrome, pancreatic insufficiency,
pheochromacytoma, scleroderma, somatization disorder, Zollinger-Ellison Syndrome, or other gastrointestinal inflammatory condition.
135. The method of claim 127 wherein said liver disease is chronic liver disease.
136. The method of claim 127 wherein said cancer is liver cancer, breast cancer,
cholangio carcinoma, colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, bone cancer, or blood cancer.
137. The method of claim 127 wherein said inflammatory disease is allergic airway inflammation,
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